AU2003297562A1 - COMPOUNDS WITH MIXED PDE-INHIBITORY AND Beta-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE - Google Patents

COMPOUNDS WITH MIXED PDE-INHIBITORY AND Beta-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE Download PDF

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AU2003297562A1
AU2003297562A1 AU2003297562A AU2003297562A AU2003297562A1 AU 2003297562 A1 AU2003297562 A1 AU 2003297562A1 AU 2003297562 A AU2003297562 A AU 2003297562A AU 2003297562 A AU2003297562 A AU 2003297562A AU 2003297562 A1 AU2003297562 A1 AU 2003297562A1
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Gregory S. Hamilton
Harry Jefferson Leighton
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Artesian Therapeutics Inc
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20Oxygen atoms
    • C07D215/22Oxygen atoms attached in position 2 or 4
    • C07D215/227Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/06Antiarrhythmics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84Nitriles
    • C07D213/85Nitriles in position 3
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D215/00Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20Oxygen atoms
    • C07D215/22Oxygen atoms attached in position 2 or 4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70One oxygen atom
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D237/00Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Quinoline Compounds (AREA)
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Description

WO 2004/050657 PCT/US2003/037812 COMPOUNDS WITH MIXED PDE-INHIBITORY AND p-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITY FOR TREATMENT OF HEART FAILURE 5 This application claims the benefit of U.S. Provisional Patent Application No. 60/429,344, filed November 27, 2002, the entire contents of which are herein incorporated by reference. Congestive heart failure affects an estimated 4.8 million Americans with over 400,000 new cases diagnosed each year. Despite incremental advances in drug therapy, 10 the prognosis for patients with advanced heart failure remains poor with annual mortality exceeding 40 percent. Although heart transplantation is an effective therapy for patients with advanced heart failure, less than 2,200 heart transplants are performed annually due to a limited supply of donor organs. Recent analyses indicate that further increases in the incidence and prevalence of advanced heart failure are likely, highlighting the pressing 15 need for novel and effective therapeutic strategies. During heart failure, there is an alteration of calcium homeostasis, including impaired sarcoplasmic reticulum calcium re-uptake, increased basal (diastolic) calcium levels, decreased peak (systolic) calcium and reduced rate of calcium transients, resulting in a decreased force of contraction and a slowing of relaxation. The end results of these 20 abnormalities in calcium homeostasis are depressed contractile function (decreased contractility and cardiac output), impaired ventricular relaxation, and myocyte loss via ischemia and/or apoptosis-related mechanisms. Disregulation of calcium homeostasis has also been implicated in a number of other disease states, including stroke, epilepsy, ophthalmic disorders, and migraine. 25 Beta-adrenergic blocking agents are common therapy for patients with mild to moderate chronic heart failure (CHF). Some patients on p-blockers may subsequently decompensate, however, and would need acute treatment with a positive inotropic agent. Phosphodiesterase inhibitors (PDEI), such as inilrinone or enoximone, retain their full hemodynamic effects in the face of beta-blockade, because the site of PDEI action 30 (cAMP) is downstream of the p-adrenergic receptor, and because p-antagonism reverses receptor pathway desensitization changes, which are detrimental to phosphodiesterase inhibitor response. 1 WO 2004/050657 PCT/US2003/037812 SUMMARY OF THE INVENTION This invention provides compounds that possess inhibitory activity against p adrenergic receptors and phosphodiesterase PDE, including phosphodiesterase 3 (PDE3). This invention further provides pharmaceutical compositions comprising such 5 compounds; methods of using such compounds for treating cardiovascular disease, stroke, epilepsy, ophthalmic disorder or migraine; and methods of preparing pharmaceutical compositions and compounds that possess inhibitory activity against p-adrenergic receptors and PDE. 10 DETAILED DESCRIPTION DEFINITIONS "Alkyl radicals" refer to radicals of branched and unbrached saturated hydrocarbon chains comprising a designated number of carbon atoms. For example, Cl
C
9 alkyl radicals designates radicals of straight and branched hydrocarbon chains 15 containing from 1 to 9 carbon atoms and includes all isomers. In some embodiments of the present invention, the alkyl radials are C 1
-C
12 radicals, and in other embodiments they are C 1
-C
6 radicals. In yet other embodiments, the alkyl radicals are chosen from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. "Alkenyl radicals" refer to radicals of branched and unbranched unsaturated 20 hydrocarbon chains comprising a designated number of carbon atoms. For example, C 2 C 9 alkenyl radicals designates radicals of straight and branched hydrocarbon chains containing from 2 to 9 carbon atoms having at least one double bond and includes all isomers. In some embodiments of the present invention, the alkenyl radicals are C2-C6, and in others they are C 3
-C
9 . In yet other embodiments, the alkenyl radicals are chosen 25 from ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl, and n-hexenyl. "Alkynyl radicals" refer to radicals of branched and unbranched unsaturated hydrocarbon chains comprising a designated number of carbon atoms containing a triple bond between at least two carbon atoms and includes all isomers. For example, a C2-C9 30 alkynyl designates straight and branched hydrocarbon chains containing from 2 to 9 carbon atoms having at least one triple bond and includes all isomers. In some 2 WO 2004/050657 PCT/US2003/037812 embodiments of the present invention, the alkynyl radicals are C 2
-C
6 , and in others they are C 3
-C
9 . In some embodiments, the alkynyl radicals are chosen from ethynyl, propynyl, iso-propynyl, butynyl, iso-butynyl, tert-butynyl, and pentynyl, and hexynyl. "Alkylene radicals" refer to bivalent radicals of alkanes and includes all isomers. 5 "Alkenylene radicals" refer to bivalent radicals of alkenes having at least one double bond and includes all isomers. "Alkynylene radicals" refer to bivalent radicals of alkynes having a triple bond between at least two carbon atoms and includes all isomers. "Cycloalkyl radicals" refer to cyclic alkyl radicals having a designated number of 10 carbon atoms. For example, Cl-C 8 cycloalkyl radicals designates radicals of straight and branched hydrocarbon chains containing from 1 to 8 carbon atoms and includes all isomers. In some embodiments of the present invention, the cycloalkyl radials are Ci-C6 radicals, and in other embodiments they are C 1
-C
4 radicals. In yet other embodiments, the alkyl radicals are chosen from methylcyclopropane, ethylcyclopropane, 15 propylcyclopropane, butylcyclopropane, pentylcyclopropane, methylcyclobutane, ethylcyclobutane, propylcyclobutane, butylcyclobutane, methylcyclopentane, ethylcyclopentane, propylcyclopentane, methylcyclohexane, ethylcyclohexane, cyclopentyl, cyclobutyl, cycopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. "Cycloalkenyl radicals" refer to cyclic alkyl radicals having a designated number 20 of carbon atoms and at least one double bond. For example, C 2
-C
8 cycloalkenyl radicals designates radicals of straight and branched hydrocarbon chains containing from 2 to 8 carbon atoms, having at least one double bond and includes all isomers. In some embodiments of the present invention, the cycloalkenyl radials are C 2
-C
6 radicals. In yet other embodiments, the alkyl radicals are chosen from methylcyclopentene, 25 ethylcyclopentene, propylcyclopentene, methyleyclohexene, ethylcyclohexene, cycopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. "Cycloalkynyl radicals" refer to cyclic alkyl radicals having a designated number of carbon atoms and at least one triple bond. For example, C 2
-C
8 cycloalkynyl radicals designates radicals of straight and branched hydrocarbon chains containing from 2 to 8 30 carbon atoms, having at least one triple bond and includes all isomers. In some embodiments of the present invention, the cycloalkynyl radials are C 2
-C
6 radicals. In yet 3 WO 2004/050657 PCT/US2003/037812 other embodiments, the alkyl radicals are chosen from methylcyclohexyne, ethylcyclohexyne, cyclohexynyl, cycloheptenynyl, and cyclooctenynyl. "Alkylthio" refers to a sulfur substituted alkyl radical. "Alkoxy" refers to the group -OR, wherein R is an alkyl radical as defined above. 5 In some embodiments of the present invention, R is chosen from branched and unbranched saturated hydrocarbon chains containing from I to 9 carbon atoms. In some embodiments, R is chosen from alkyl radicals like Ci-C 6 and C 3
-C
9 . In yet other embodiments, the alkyl radicals are chosen from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. 10 "Aryl" refers to aromatic, hydrocarbon cyclic moieties having one or more closed rings. For example, aryl may be chosen from C 6 to C 24 and from CIO to C 18 aromatic hydrocarbon cyclic moieties. In some embodiments, aryl is chosen from phenyls, benzyls, naphthyls, anthracenyls, phenanthracenyls, and biphenyls. In yet other embodiments, aryl is chosen from phenyl, benzyl, naphthyl, anthracenyl, 15 phenanthracenyl, and biphenyl. "Heteroaryl" refers to aromatic, cyclic moieties having one or more closed rings with one or more heteroatoms (for example, sulfur, nitrogen or oxygen) in at least one of the rings. For example, heteroaryl may be chosen from 5- to 7-membered monocyclic and bicyclic or 7- to 14-membered bicyclic ring systems containing carbon atoms and 1, 20 2, 3 or 4 heteroatoms independently chosen from a nitrogen atom, an oxygen atom, and a sulfur atom. In some embodiments, heteroaryl radicals are chosen from pyrroles, furanyls, thiophenes, pyridines and isoxazoles. In yet other embodiments, heteroaryl is chosen from radicals of furans, benzofurans, benzothiophenes, oxazoles, thiazoles, and benzopyrans. 25 "Halo radicals" refers to fluoro, chloro, bromo, and iodo radicals. "Substituted phenyl" refers to phenyls that are substituted with one or more substituents. For example, the substituents may be chosen from Ci-C 6 alkyl radicals, C 2 C 6 alkenyl radicals, C 2
-C
6 alkynyl radicals, CI-C 6 alkoxy radicals, C 2
-C
6 alkenyloxy radicals, phenoxy, benzyloxy, hydroxy, carboxy, hydroperoxy, carbamido, carbamoyl, 30 carbamyl, carbonyl, carbozoyl, amino, hydroxyamino, formamido, formyl, guanyl, cyano, cyanoamino, isocyano, isocyanato, diazo, azido, hydrazino, triazano, nitrilo, nitro, nitroso, isonitroso, nitrosamino, imino, nitrosimino, oxo, C 1
-C
6 alkylthio, sulfamino, 4 WO 2004/050657 PCT/US2003/037812 sulfamoyl, sulfeno, sulfhydryl, sulfinyl, sulfo, sulfonyl, thiocarboxy, thiocyano, isothiocyano, thioformamido, halo, haloalkyl, chlorosyl, chloryl, perchloryl, trifluoromethyl, iodosyl, iodyl, phosphino, phosphinyl, phospho, phosphono, arsino, selanyl, disilanyl, siloxy, silyl, silylene and carbocyclic and heterocyclic moieties. 5 "Effective amount" refers to the amount sufficient to produce a desired effect. For example, an effective amount for treating heart failure is an amount sufficient to treat heart failure; an effective amount for treating chronic heart failure is an amount sufficient to treat chronic heart failure; an effective amount for inhibiting PDE is an amount sufficient to inhibit PDE; an effective amount for inhibiting PDE 3 is an amount sufficient 10 to inhibit PDE 3; and an effective amount for inhibiting p-adrenergic receptors is an amount sufficient to inhibit the p-adrenergic receptors. "Metabolite" refers to a substance produced by metabolism or by a metabolic process. "Pharmaceutically-acceptable carrier" refers to a phannaceutically-acceptable 15 materials, compositions, and vehicles, such as liquid and solid fillers, diluents, excipients, and solvent encapsulating materials, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and being suitable for use with the patient. A 20 pharmaceutically-acceptable carrier may be active or inactive with respect to the patient. In some embodiements, pharmaceutically-acceptable carrier are chosen from: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose band its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) 25 excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic 30 acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or 5 WO 2004/050657 PCT/US2003/037812 polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. "Pharmaceutically acceptable equivalent" includes, without limitation, phannaceutically acceptable salts, hydrates, solvates, metabolites, prodrugs, and isosteres. 5 Many pharmaceutically acceptable equivalents are expected to have the same or similar in vitro or in vivo activity as the compounds of the invention. "Pharmaceutically acceptable salt" refers to acid and base salts of the inventive compounds, which salts are neither biologically nor otherwise undesirable. In some embodiments, the salts can be formed with acids, and in some embodiments the salts can 10 be formed form acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2 hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, 15 nicotinate, oxalate, thiocyanate, tosylate and undecanoate. In some embodiments, the salts can be formed from base salts, and in other embodiments the salts can be formed from ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as 20 arginine and lysine. In some embodiments, the basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl 25 bromides. "Prodrug" refers to a derivative of the inventive compounds that undergoes biotransformation, such as metabolism, before exhibiting its pharmacological effect(s). The prodrug is formulated with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of 30 action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). The prodrug can be readily prepared from the inventive compounds, using conventional methodology described, for 6 WO 2004/050657 PCT/US2003/037812 instance, in BURGER'S MEDICINAL CHEMISTRY AND DRUG CHEMISTRY (5th ed.), volume 1 at pages 172-178, 949-982 (1995) (the disclosure of which is incorporated herein by reference). "Isosteres" refer to elements, functional groups, substitutents, molecules or ions 5 having different molecular formulae but exhibiting similar or identical physical properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they have different molecular formulae. Typically, two isosteric molecules have similar or identical volumes and shapes. Ideally, isosteric compounds should be isomorphic and able to co-crystallize. Other physical 10 properties that isosteric compounds often share include boiling point, density, viscosity and thermal conductivity. However, certain properties may be different, such as dipolar moments, polarity, polarization, size and shape, since the external orbitals may be hybridized differently. The term "isosteres" encompasses "bioisosteres," which, in addition to their physical similarities, share some biological properties. Typically, 15 bioisosteres interact with the same recognition site or produce broadly similar biological effects. "Stereoisomers" are isomers that differ only in the arrangement of the atoms in space. "Enantiomers" are stereoisomers that are non-superimposable mirror images of 20 one another. "Enantiomer-enriched" is a phrase that denotes a mixture in which one enantiomer predominates. "Animal" refers to a living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Examples 25 include, without limitation, members of the human, equine, porcine, bovine, murine, canine, and feline species. In the case of a human, an "animal" may also be referred to as a "patient." "Mammal" refers to a warm-blooded vertebrate animal. "Treating" refers to: (i) preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not 30 yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition. 7 WO 2004/050657 PCT/US2003/037812 "Heart failure" refers to the pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues. "Congestive heart failure" refers to heart failure that results in the development of 5 congestion and edema in the metabolizing tissues. "Hypertension" refers to elevation of systemic blood pressure. "SA/AV node disturbance" refers to an abnormal or irregular conduction and/or rhythm associated with the sinoatrial (SA) node and/or the atrioventricular (AV) node. "Arrhythmia" refers to abnormal heart rhythm. In arrhythmia, the heartbeats may 10 be too slow, too fast, too irregular or too early. Examples of arrhythmia include, without limitation, bradycardia, fibrillation (atrial or ventricular) and premature contraction. "Hypertrophic subaortic stenosis" refers to enlargement of the heart muscle due to pressure overload in the left ventricle resulting from partial blockage of the aorta. "Angina" refers to chest pain associated with partial or complete occlusion of one 15 or more coronary arteries in the heart. Unless the context clearly dictates otherwise, the definitions of singular terms may be extrapolated to apply to their plural counterparts as they appear in the application; likewise, the definitions of plural terms may be extrapolated to apply to their singular counterparts as they appear in the application. 20 COMPOUNDS This invention provides compounds of formula (I) p-(Ar)n-(L)m -X (I) 25 or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: m is chosen from 0 and 1; n is chosen from 0 and 1; P is chosen from a 2-amino-i -hydroxyeth- 1 -yl radical, N-substituted-2-amino- 1 30 hydroxyeth- 1 -yl radicals, N-N-disubstituted-2-amino- 1 -hydroxyeth- 1 -yl radicals, a 3 8 WO 2004/050657 PCT/US2003/037812 amino-2-hydroxypropoxy radical, N-substituted-3-amino-2-hydroxypropoxy radicals, and N-N-disubstituted-3-amino-2-hydroxypropoxy radicals; Ar is chosen from aryl radicals and heteroaryl radicals, which aryl and heteroaryl radicals are optionally substituted with one to three substituent(s) chosen from R 2 , R 3 , and 5 R 4 ;
R
2 , R 3 , and R 4 are independently chosen from C 1
-C
8 alkyl radicals, C 2
-C
8 alkenyl radicals, C 2
-C
8 alkynyl radicals, Ci-C 4 alkylthio groups, C1-C 4 alkoxy groups, halo radicals, a nitro group, a cyano group, a trifluoromethyl group, -NR 5
R
6 groups, acylaminoalkyl radicals, -NHSO 2
R
1 groups and -NHCONHR 1 groups, wherein one or 10 more -CH 2 - group(s) of the alkyl, alkenyl and alkynyl radicals is/are optionally replaced with -0-, -S-, -SO 2 - and/or -NR 5 -, and the alkyl, alkenyl and alkynyl radicals are optionally substituted with one or more substituent(s) chosen from an oxo group and a hydroxyl group;
R
5 and R 6 are independently chosen from a lone pair of electrons, a 15 hydrogen radical, C 1
-C
8 alkyl radicals, C 2
-C
8 alkenyl radicals and C 2
-C
8 alkynyl radicals, wherein the alkyl, alkenyl and alkynyl radicals are optionally substituted with a substituent chosen from a phenyl radical and substituted phenyl radicals;
R
1 is chosen from CI-C 8 alkyl radicals, C 3
-C
8 cycloalkyl radicals, C 2
-C
8 20 alkenyl radicals, C 3
-C
8 cycloalkenyl radicals, C 2
-C
8 alkynyl radicals and C 3
-C
8 cycloalkynyl radicals; L is chosen from a direct bond, C 1
-C
1 2 alkylene radicals, C 2
-C
12 alkenylene radicals and C 2
-C
1 2 alkynylene radicals, wherein one or more -CH 2 - group(s) of the alkylene, alkenylene and alkynylene radicals is/are optionally replaced with -0-, -S-, 25 SO 2 - and/or -NR 5 -, and the alkylene, alkenylene and alkynylene radicals are optionally substituted with one or more substituent(s) independently chosen from an oxo group and a hydroxyl group; and X is chosen from moieties of formulas A-Q: 9 WO 2004/050657 PCT/US2003/037812 R R R N A RR N R NO R\/ R R B R RR N~NR- J- >= N H R c D RR0 RN H R N N O R O R-- 0/0 NNH R R L M E F- RG 5 R R R R R NR N N 1 R 0 R:'N.-~ R ~N R N-NH H R H R -- 0 0 NN RH N~ N R 0 R N. N I/X 0 R RA) R I R~ K L R M 10 10 WO 2004/050657 PCT/US2003/037812 R R--R R R NR O R N P R N N-NH / 0 N R R R Q wherein one R group of moieties A-Q forms a covalent bond between X and L when m is 1, or between X and Ar when n is 1 and m is 0, or 5 between X and p when n is 0 and m is 0; and each remaining R group of moieties A-Q is independently chosen from a hydrogen radical, halo radicals, a nitro group, a cyano group, a trifluoromethyl group, an amino group, NR 5
R
6 groups, Ci-C 4 alkoxy radicals, C 1
-C
4 alkylthio radicals,
COOR
1 radicals, C 1
-C
12 alkyl radicals, C 2
-C
12 alkenyl radicals and C 2
-C
12 10 alkynyl radicals, wherein one or more -CH 2 - group(s) of the alkyl, alkenyl and alkynyl radicals is/are optionally replaced with -0-, -S-, -SO 2 - and/or NR 5 -, and the alkyl, alkenyl and alkynyl radicals are optionally substituted with one or more substituent(s) chosen from an oxo group and a hydroxyl group; and 15 with the following provisos: (a) when m+n is 0, when X is chosen from A moieties, when p is chosen from a 2-amino-1 -hydroxyeth- l-yl radical, N-substituted-2-amino 1 -hydroxyeth- 1 -yl radicals, and N-N-disubstituted-2-amino- 1 -hydroxyeth 1-yl radicals, and 20 (i) when p is at position 3 or 4 of A, 11 WO 2004/050657 PCT/US2003/037812 5 4 6 () , 3 7 N 0 8 H 1 then the N-substituted-2-amino-1-hydroxyeth-1 -yl radicals are not substituted with an alkyl radical, a cycloalkyl radical; an alkenyl radical; a cycloalkenyl radical, or an alkynyl radical; 5 and then one substituent of the N-N-disubstituted-2-amino- 1 hydroxyeth- 1 -yl radicals is not an alkyl radical, a cycloalkyl radical; an alkenyl radical; a cycloalkenyl radical, or an alkynyl radical; (ii) when P is at position 5 of A, then position 8 of A is not substituted with an alkoxy radical or a hydroxyl radical; 10 (iii) when P is at position 6 of A, position 8 of A is not substituted with an alkoxy radical, an acyloxy radical, or a hydroxyl radical; and (iv) when P is at position 8 of A and position 5 of A is substituted with an alkoxy radical or a hydroxy radical, then the N 15 substituted-2-amino-1-hydroxyeth-1-yl radicals are not substituted with an alkyl radical or a cycloalkyl radical; and then one substituent of the N-N-disubstituted-2-amino-1 hydroxyeth-1 -yl radicals is not an alkyl radical or a cycloalkyl radical 20 (b) when m+n is 0, when X is chosen from A moieties, when P is chosen from a 3-amino-2-hydroxypropoxy radical, N-substituted-3-amino 2-hydroxypropoxy radicals, and N-N-disubstituted-3 -amino-2 hydroxypropoxy radicals, and (i) when P is at position 4 of A, then any R attached to the 25 ring nitrogen is not a Ci-C 3 alkyl radical or a Ci-C 3 alkenyl radical; (ii) when P is at any position 5-8 of A, then the N substituted-3-amino-2-hydroxypropoxy radicals are not substituted 12 WO 2004/050657 PCT/US2003/037812 with an alkyl radical; a cycloalkyl radical; an alkenyl radical; a cycloalkenyl radical; or an alkynyl radical; and then one substituent of the N-N-disubstituted-3-amino-2 hydroxypropoxy radicals is not an alkyl radical; a cycloalkyl radical; 5 an alkenyl radical; a cycloalkenyl radical; or an alkynyl radical; (c) when m is 1, when n is 0, when X is chosen from A moieties, when P is chosen from a 3-amino-2-hydroxypropoxy radical, N-substituted-3 amino-2-hydroxypropoxy radicals, and N-N-disubstituted-3-amino-2 hydroxypropoxy radicals, and when p is at position 5 of A, and position 8 10 of A is substituted with a hydrogen radical, an alkoxy radical, or an aryloxy radical, and the R attached to the ring nitrogen is a hydrogen radical or an alkyl radical, then L is not a C 3 alkenyl radical; and (d) when m+n is 0, when X is chosen from J moieties, when P is chosen from a 3-amino-2-hydroxypropoxy radical, N-substituted-3-amino 15 2-hydroxypropoxy radicals, and N-N-disubstituted-3-amino-2 hydroxypropoxy radicals, and when P is attached to the phenyl ring of J, then the N-substituted-3-amino-2-hydroxypropoxy radicals and the N-N disubstituted-3-amino-2-hydroxypropoxy radicals are not substituted with a C 3
-C
4 alkyl radical or a phenethyl radical. 20 Every variable substituent is defined independently at each occurrence. Thus, the definition of a variable substituent in one part of a formula is independent of its definition(s) elsewhere in that formula and of its definition(s) in other formulas. In formula (I), moieties A, G, J-L, and O-Q contain dashed lines in their respective structures. These dashed lines indicate that saturation is optional. 25 In formula (I)'s 1, the N-substituted-2-amino- 1 -hydroxyeth- 1 -yl radicals, the N-N disubstituted-2-amino-1-hydroxyeth-1-yl radicals, the N-substituted-3-amino-2 hydroxypropoxy radicals, and N-N-disubstituted-3-amino-2-hydroxypropoxy radicals may be substituted with any group capable of bonding to such radicals. In some embodiments, formula (I)'s L is chosen from C-C 12 alkylene radicals, 30 C 2 -Cu alkenylene radicals, and C 2
-C
1 2 alkynylene radicals. In some embodiments, formula (I)'s L is chosen from C-C 8 alkylene radicals, C 2
-C
8 alkenylene radicals, and
C
2
-C
8 alkynylene radicals. In some embodiments, one or more -CH 2 - group(s) of the 13 WO 2004/050657 PCT/US2003/037812 alkylene, alkenylene and alkynylene radicals is/are optionally replaced with -0- and/or
-NR
5 -, and the alkylene radicals are optionally substituted with one or more oxo group(s). In some embodiments, formula (I)'s L is chosen from C 1
-C
8 alkylene radicals. In some embodiments, formula (I)'s L is chosen from -O(CH 2
)
3 0-, -O(CH 2
)
3
NH(CO)CH
2 0-, and 5 -O(CH 2
)
3
NH(CO)(CH
2
)
3 0-. In some embodiments, formula (I)'s X is chosen from moieties of formulas B, E, and 0. In some embodiments, formula (I)'s X is chosen from moieties of formula A, when n is 1. In some embodiments, formula (I)'s X is chosen from moieties of formula J, when m+n is 1 or 2. 10 In some embodiments, formula (I)'s R groups of moieties A-Q are independently chosen from a hydrogen radical; C 1
-C
1 2 alkyl radicals; C 2
-C
1 2 alkenyl radicals; C 2
-C
1 2 alkynyl radicals, halo radicals and cyano group. In some embodiments, formula (I)'s R groups of moieties A-Q are independently chosen from a hydrogen radical; C 1
-C
6 alkyl radicals; C 2
-C
6 alkenyl radicals; C 2
-C
6 alkynyl radicals, halo radicals and cyano group. 15 In some embodiments, formula (I)'s R 1 is chosen from C 1
-C
6 alkyl radicals, C 1
-C
6 cycloalkyl radicals, C 2
-C
6 alkenyl radicals, C 2
-C
6 cycloalkenyl radicals, and C 2
-C
6 alkynyl radicals. In some embodiments, formula (I)'s R 2 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl 20 radicals, C 1
-C
4 alkoxy groups; C 1
-C
4 alkylthio groups; C 1
-C
8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C1-C 6 . In some embodiments, formula (I)'s R 3 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl 25 radicals, C 1
-C
4 alkoxy groups; C 1
-C
4 alkylthio groups; CI-C 8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C 1
-C
6 . In some embodiments, formula (I)'s R 4 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl 30 radicals, C 1
-C
4 alkoxy groups; C 1
-C
4 alkylthio groups; C 1
-C
8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C 1
-C
6 . 14 WO 2004/050657 PCT/US2003/037812 In some embodiments, formula (I)'s R 5 is chosen from a lone pair of electrons; a hydrogen radical; C 1
-C
8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, formula (I)'s R 6 is chosen from a lone pair of electrons; a hydrogen radical; C 1
-C
8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. 5 In some embodiments, formula (I)'s Ar is chosen from phenyl radicals, naphthyl radicals, pyridyl radicals, isoxazoyl radicals, pyridyl radicals, quinolyl radicals, and isoquinolyl radicals. In other embodiments, the heteroaryl radicals are chosen from radicals of furans, benzofurans, benzothiophenes, oxazoles, thiazoles, and benzopyrans. In some embodiments, formula (I)'s Ar is chosen from groups Ari-Ar 7 : 10 V(a)) a O (CH 2 )n N0O)(a) V = 0, C=0, S, N, CH 2 (a) (a) N N n = 1-3 Ar 1 Ar 2 (cx Ar 3 Ar 4 (a) a)(() U 0 (a)~ N ((X)) W =)0, S, N U = -CH 2
CH
2 -, U -CH 2
CH
2 -, -CH=CH=, -CH=CH=, 0, S, N, or a bond 0, S, N, or a bond Ar 5 ArN Ar wherein (a) indicates the position where Ar may bond to 3, L, and X. Since the compounds of the present invention may possess one or more 15 asymmetric carbon center(s), they may be capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures of optical isomers. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes. One such process entails formation of diastereoisomeric salts, by treatment with an optically active acid or base, and then separation of the mixture of 20 diastereoisomers by crystallization, followed by liberation of the optically active bases 15 WO 2004/050657 PCT/US2003/037812 from these salts. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid. A different process for separating optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. 5 Still another available method involves synthesis of covalent diastereoisomeric molecules, for example, esters, amides, acetals, and ketals, by reacting the compounds of the present invention with an optically active acid in an activated form, an optically active diol or an optically active isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or 10 sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. In some cases hydrolysis to the "parent" optically active drug is not necessary prior to dosing the patient, since the compound can behave as a prodrug. The optically active compounds of the present invention likewise can be obtained by utilizing optically active starting materials. 15 It is understood that the compounds of the present invention encompass individual optical isomers as well as racemic and non-racemic mixtures. Accordingly, in some embodiments, formula (I)'s P is chosen from a 2-amino-I hydroxyeth- 1 -yl radical, N-substituted-2-amino- 1 -hydroxyeth- 1 -yl radicals, and N-N disubstituted-2-amino- 1 -hydroxyeth- 1 -yl radicals, wherein the carbon at position 1 of 20 each radical is enriched over its mirror image counterpart. In some embodiments, the R configuration is enriched. In some embodiments, formula (I)'s P is chosen from a 3-amino-2 hydroxypropoxy radical, N-substituted-3-amino-2-hydroxypropoxy radicals, and N-N disubstituted-3-amino-2-hydroxypropoxy radicals, wherein the carbon at position 2 of 25 each radical is enriched over its mirror image counterpart. In some embodiments, the S configuration is enriched. In some embodiments, m+n is 0. In other embodiments, m+n is 1. In other embodiments, m+n is 2. In another embodiment, a compound of present invention is chosen from those of 30 formula (I) as defined above, pharmaceutically acceptable equivalents and stereoisomers thereof, wherein: m is chosen from 0 and 1; 16 WO 2004/050657 PCT/US2003/037812 n is chosen from 0 and 1; p is chosen from radicals of formula (Pi) and radicals of formula (P2):
-CHOHCH
2
NZ
1
Z
2 (P i) and
-OCH
2
CHOHCH
2
NZ
1
Z
2 ($2); 5 wherein Z 1 and Z 2 are independently chosen from a hydrogen radical, R 1 radicals, and -CH 2
CH
2
-Y-R
1 radicals; wherein R 1 is as defined above; wherein Y is chosen from a -NHCO- radical, a -NHCONH- radical, and a -NHSO 2 - radical; 10 Ar is as defined above; L is as defined above; and X is as defined above; with the following provisos: (a) when m+n is 0, when X is chosen from A moieties, when P is 15 chosen from 1 radicals, and (i) when 1 is at position 3 or 4 of A, 5 4 N 0 8 H 1 then one of pi's Z1 or Z 2 is not an R 1 radical; (ii) when Pi is at position 5 of A, then position 8 of A is not 20 substituted with an alkoxy radical or a hydroxyl radical; (iii) when Pi is at position 6 of A, position 8 of A is not substituted with an alkoxy radical, an acyloxy radical, or a hydroxyl radical; and (iv) when P1 is at position 8 of A and position 5 is substituted with an alkoxy radical or a hydroxy radical, then one of pi's Z 1 or Z 2 is 25 not an alkyl radical or a cycloalkyl radical; (b) when m+n is 0, when X is chosen from A moieties, when P is chosen from P2, and 17 WO 2004/050657 PCT/US2003/037812 (i) when P2 is at position 4 of A, then any R attached to the ring nitrogen is not a C1-C 3 alkyl radical or a C1-C 3 alkenyl radical; (ii) when P2 is at any position 5-8 of A, then one of P2's Z 1 or Z 2 is not an alkyl radical; a cycloalkyl radical; an alkenyl radical; 5 a cycloalkenyl radical; or an alkynyl radical; (c) when m is 1, when n is 0, when X is chosen from moieties of formula A, when L is attached to position 5 of A, when position 8 of A is substituted with a hydrogen radical, an alkoxy radical, or an aryloxy radical, and when the R attached to the ring nitrogen is a hydrogen radical 10 or an alkyl radical, then L is not a C 3 alkenyl radical; and (d) when m+n is 0, when X is chosen from J moieties, when P is chosen from P2, when P2 is attached to the phenyl ring of J, then P2's Z 1 and Z 2 are not a C 3
-C
4 alkyl radical or a phenethyl radical. In some embodiments, formula (I)'s L is chosen from CI-C 12 alkylene radicals, 15 C 2
-C
12 alkenylene radicals, and C 2
-C
12 alkynylene radicals. In some embodiments, formula (I)'s L is chosen from C-C 8 alkylene radicals, C 2
-C
8 alkenylene radicals, and
C
2
-C
8 allynylene radicals. In some embodiments, one or more -CH 2 - group(s) of the alkylene, alkenylene and alkynylene radicals is/are optionally replaced with -0- and/or
-NR
5 -, and the alkylene radicals are optionally substituted with one or more oxo group(s). 20 In some embodiments, formula (I)'s L is chosen from C-Cs alkylene radicals. In some embodiments, formula (I)'s L is chosen from -O(CH 2
)
3 0-, -O(CH 2
)
3
NH(CO)CH
2 0-, and
-O(CH
2
)
3
NH(CO)(CH
2
)
3 0-. In some embodiments, formula (I)'s X is chosen from moieties of formulas B, E, and 0. In some embodiments, formula (I)'s X is chosen from moieties of formula A, 25 when n is 1. In some embodiments, formula (I)'s X is chosen from moieties of formula J, when m+n is 1 or 2. In some embodiments, formula (I)'s R groups of moieties A-Q are independently chosen from a hydrogen radical; C-C 1 2 alkyl radicals; C 2
-C
12 alkenyl radicals; and C 2
-C
12 alkynyl radicals., In some embodiments, formula (I)'s R groups of moieties A-Q are 30 independently chosen from a hydrogen radical; C-C 6 alkyl radicals; C 2
-C
6 alkenyl radicals; and C 2
-C
6 alkynyl radicals. 18 WO 2004/050657 PCT/US2003/037812 In some embodiments, formula (I)'s R 1 is chosen from C-C 6 alkyl radicals, C-C 6 cycloalkyl radicals, C 2
-C
6 alkenyl radicals, C 2
-C
6 cycloalkenyl radicals, and C 2
-C
6 alkynyl radicals. In some embodiments, formula (I)'s R 2 is chosen from a cyano group; a nitro 5 group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C-C 4 alkoxy groups; CI-C 4 alkylthio groups; C-C 8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C I-C 6 . In some embodhents, formula (I)'s R 3 is chosen from a cyano group; a nitro 10 group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C-C 4 alkoxy groups; CI-C 4 alkylthio groups; CI-C 8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2 -Cs alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C-C 6 . In some embodiments, formula (I)'s R4 is chosen from a cyano group; a nitro 15 group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C-C 4 alkoxy groups; C-C 4 alkylthio groups; C-C 8 alkyl radicals; C 2 -CS alkenyl radicals; and C 2 -Cs alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C -C 6 . In some embodiments, formula (I)'s R 5 is chosen from a lone pair of electrons; a 20 hydrogen radical; C-Cs alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, formula (I)'s R 6 is chosen from a lone pair of electrons; a hydrogen radical; C-Cs alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, formula (I)'s Ar is chosen from phenyl radicals, naphthyl radicals, pyridyl radicals, isoxazoyl radicals, pyridyl radicals, quinolyl radicals, and 25 isoquinolyl radicals. In other embodiments, Ar is a heteroaryl chosen from radicals of furans, benzofurans, benzothiophenes, oxazoles, thiazoles, and benzopyrans. In some embodiments, formula (I)'s Ar is chosen from groups Ar-Ar 7 as defined above. In some embodiments, the compound of the present invention is chosen from pharmaceutically acceptable salts of compounds of formula (I). 30 In some embodiments, the compound of the present invention is chosen from hydrates of compounds of formula (I). 19 WO 2004/050657 PCT/US2003/037812 In some embodiments, the compound of the present invention is chosen from solvates of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from metabolites of compounds of formula (I). 5 In some embodiments, the compound of the present invention is chosen from prodrugs of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from isosteres of compounds of formula (I). In some embodiments, formula (I)'s Zi and Z 2 are the same. In other 10 embodiments, in formula (II), Z, and Z 2 differ. In some embodiments, formula (I)'s Z 1 and Z 2 are chosen from R 1 radicals, and in other embodiments, formula (I)'s Zi and Z 2 are chosen from -CH 2
CH
2
-Y-R
1 radicals. In some embodiments, formula (I)'s P is chosen from radicals of formula (pi*) and radicals of formula (P2*): 15 -C*HOHCH 2 NZiZ 2 ($1*) and
-OCH
2
C*HOHCH
2
NZIZ
2 ($2*); wherein the * on the Cs in 11* and p2* denote chiral centers that are enriched over their respective mirror image counterparts. In some embodiments, formula (I)'s * on the C in 11* denotes a chiral-carbon center that is enriched in the R configuration. In some 20 embodiments, formula (I)'s * on the C in p2* denotes a chiral-carbon center that is enriched in the S configuration. In some embodiments, m+n is 0. In other embodiments, m+n is 1. In other embodiments, m+n is 2. In another embodiment, a compound of present invention is chosen from those of 25 formula (I) as defined above, pharmaceutically acceptable equivalents and stereoisomers thereof, wherein: m is chosen from 0 and 1; n is chosen from 0 and 1; P is chosen from radicals of formula (pi) and radicals of formula (P2) as defined 30 above; Ar is as defined above; 20 WO 2004/050657 PCT/US2003/037812 L is chosen from a -CH 2
CH
2 - radical, a -CH(CH 3
)CH
2 - radical, and a
-CH(CH
3
)
2
CH
2 -radical; and X is as defined above. In some embodiments, formula (I)'s R groups of moieties of formula B-I and K-Q 5 are independently chosen from a hydrogen radical; C-C 1 2 alkyl radicals; C 2
-C
12 alkenyl radicals; and C 2
-C
12 alkynyl radicals. In some embodiments, formula (I)'s R groups of moieties of formula B-I and K-Q are independently chosen from a hydrogen radical; C
C
6 alkyl radicals; C 2
-C
6 alkenyl radicals; and C 2
-C
6 alkynyl radicals. In some embodiments, formula (I)'s R 1 is chosen from C-C 6 alkyl radicals, C-C 6 10 cycloalkyl radicals, C 2
-C
6 alkenyl radicals, C 2
-C
6 cycloalkenyl radicals, and C 2
-C
6 alkynyl radicals. In some embodiments, formula (I)'s R 2 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C-C 4 alkoxy groups; C-C 4 alkylthio groups; C-C 8 alkyl radicals; C 2
-C
8 alkenyl 15 radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C-C 6 . In some embodiments, formula (I)'s R 3 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C-C 4 alkoxy groups; C-C 4 alkylthio groups; C-C 8 alkyl radicals; C 2
-C
8 alkenyl 20 radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C-C 6 . In some embodiments, formula (I)'s R 4 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C-C 4 alkoxy groups; C-C 4 alkylthio groups; C-C 8 alkyl radicals; C 2
-C
8 alkenyl 25 radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C-C 6 . In some embodiments, formula (I)'s R 5 is chosen from a lone pair of electrons; a hydrogen radical; C-Cg alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, formula (I)'s R 6 is chosen from a lone pair of electrons; a 30 hydrogen radical; C-Cs alkyl radicals; C 2 -Cs alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, formula (I)'s Ar is chosen from phenyl radicals, naphthyl radicals, pyridyl radicals, isoxazoyl radicals, pyridyl radicals, quinolyl radicals, and 21 WO 2004/050657 PCT/US2003/037812 isoquinolyl radicals. In other embodiments, Ar is a heteroaryl chosen from radicals of furans, benzofurans, benzothiophenes, oxazoles, thiazoles, and benzopyrans. In some embodiments, formula (I)'s Ar is chosen from groups Ar-Ar 7 as defined above. In some embodiments, the compound of the present invention is chosen from 5 pharmaceutically acceptable salts of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from hydrates of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from solvates of compounds of formula (I). 10 In some embodiments, the compound of the present invention is chosen from metabolites of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from prodrugs of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from 15 isosteres of compounds of formula (I). In some embodiments, formula (I)'s Zi and Z2 are the same. In other embodiments, in formula (II), Z1 and Z2 differ. In some embodiments, formula (I)'s Zi and Z2 are chosen from Ri radicals, and in other embodiments, formula (I)'s Zi and Z2 are chosen from -CH 2
CH
2
-Y-R
1 radicals. 20 In some embodiments, formula (I)'s P is chosen from radicals of formula (p1*) and radicals of formula (p2*) as defined above. In some embodiments, formula (I)'s * on the C in P3i* denotes a chiral-carbon center that is enriched in the R configuration. In some embodiments, formula (I)'s * on the C in p2* denotes a chiral-carbon center that is enriched in the S configuration. 25 In some embodiments, m+n is 0. In other embodiments, m+n is 1. In other embodiments, m+n is 2. In another embodiment, a compound of present invention is chosen from those of formula (I) as defined above, pharmaceutically acceptable equivalents and stereoisomers thereof, wherein: 30 P is chosen from radicals of formula (P1I) and radicals of formula (P2) as defined above; Ar is as defined above; 22 WO 2004/050657 PCT/US2003/037812 L is chosen from a -CH 2
CH
2 - radical, a -CH(CH 3
)CH
2 - radical, and a
-CH(CH
3
)
2
CH
2 -radical; and X is as defined above. In some embodiments, formula (I)'s R groups of moieties of formula B, E and 0 5 are independently chosen from a hydrogen radical; C 1
-C
1 2 alkyl radicals; C 2 -C12 alkenyl radicals; and C 2
-C
12 alkynyl radicals. In some embodiments, formula (I)'s R groups of moieties of formula B, E and 0 are independently chosen from a hydrogen radical; C 1
-C
6 alkyl radicals; C 2
-C
6 alkenyl radicals; and C 2
-C
6 alkynyl radicals. In some embodiments, formula (I)'s R 1 is chosen from C 1
-C
6 alkyl radicals, C 1
-C
6 10 cycloalkyl radicals, C 2
-C
6 alkenyl radicals, C 2
-C
6 cycloalkenyl radicals, and C 2
-C
6 alkynyl radicals. In some embodiments, formula (I)'s R 2 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C 1
-C
4 alkoxy groups; C 1
-C
4 alkylthio groups; C1-C 8 alkyl radicals; C 2
-C
8 alkenyl 15 radicals; and C 2 -Cs alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C I-C 6 . In some embodiments, formula (I)'s R 3 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, CI-C 4 alkoxy groups; C 1
-C
4 alkylthio groups; Ci-C 8 alkyl radicals; C 2 -Cs alkenyl 20 radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from C 1
-C
6 . In some embodiments, formula (I)'s R4 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C 1
-C
4 alkoxy groups; C 1
-C
4 alkylthio groups; C 1 -Cs alkyl radicals; C 2
-C
8 alkenyl 25 radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, the acylaminoalkyl radicals contain an alkyl chain having from CI-C 6 . In some embodiments, formula (I)'s R 5 is chosen from a lone pair of electrons; a hydrogen radical; C 1
-C
8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, formula (I)'s R 6 is chosen from a lone pair of electrons; a 30 hydrogen radical; C 1
-C
8 alkyl radicals; C 2
-C
8 alkenyl radicals; and C 2
-C
8 alkynyl radicals. In some embodiments, formula (I)'s Ar is chosen from phenyl radicals, naphthyl radicals, pyridyl radicals, isoxazoyl radicals, pyridyl radicals, quinolyl radicals, and 23 WO 2004/050657 PCT/US2003/037812 isoquinolyl radicals. In other embodiments, Ar is a heteroaryl chosen from radicals of furans, benzofurans, benzothiophenes, oxazoles, thiazoles, and benzopyrans. In some embodiments, formula (I)'s Ar is chosen from groups Ari-Ar 7 as defined above. In some embodiments, the compound of the present invention is chosen from 5 pharmaceutically acceptable salts of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from hydrates of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from solvates of compounds of formula (I). 10 In some embodiments, the compound of the present invention is chosen from metabolites of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from prodrugs of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from 15 isosteres of compounds of formula (I). In some embodiments, formula (I)'s Zi and Z 2 are the same. In other embodiments, in formula (II), Z 1 and Z 2 differ. In some embodiments, formula (I)'s Zi and Z 2 are chosen from R 1 radicals, and in other embodiments, formula (I)'s Zi and Z 2 are chosen from -CH 2
CH
2
-Y-R
1 radicals. 20 In some embodiments, formula (I)'s P is chosen from radicals of formula (p*) and radicals of formula (p2*) as defined above. In some embodiments, formula (I)'s * on the C in p1j* denotes a chiral-carbon center that is enriched in the R configuration. In some embodiments, formula (I)'s * on the C in p2* denotes a chiral-carbon center that is enriched in the S configuration. 25 In some embodiments, m+n is 0. In other embodiments, m+n is 1. In other embodiments, m+n is 2. In another embodiment of the present invention, a compound of the present invention is chosen from compounds containing a radical P and a radical X, wherein: P is chosen from a 2-amino-1-hydroxyeth-1-yl radical, N-substituted-2-amino-1 30 hydroxyeth-1-yl radicals, N-N-disubstituted-2-amino-1-hydroxyeth-1-yl radicals, a 3 amino-2-hydroxypropoxy radical, N-substituted-3-amino-2-hydroxypropoxy radicals, and 24 WO 2004/050657 PCT/US2003/037812 N-N-disubstituted-3-amino-2-hydroxypropoxy radicals, wherein the N-N-disubstituted radicals are substituted with identical substituents. In some embodiments, P is chosen from radicals of formula (1i) and radicals of formula (P2) as defined above. In some embodiments, P is chosen from radicals of 5 formula (1I*) and radicals of formula (p2*) as defined above. In some embodiments, X is chosen from moieties of formulas B, E and 0. In some embodiments, X is chosen from moieties of formula A, when n is 1. In some embodiments, X is chosen from moieties of formula J, when m+n is 1 or 2. In some embodiments, the compound of the present invention is chosen from 10 pharmaceutically acceptable salts of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from hydrates of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from solvates of compounds of formula (I). 15 In some embodiments, the compound of the present invention is chosen from metabolites of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from prodrugs of compounds of formula (I). In some embodiments, the compound of the present invention is chosen from 20 isosteres of compounds of formula (I). 25 WO 2004/050657 PCT/US2003/037812 Examples of a compound of formula (I) include without limitation: OH OH HN HN N O O N CH H HN C N H 0 (Example 1) (Example 2) 6-{2-hydroxy-3-[(methylethyl)amino]- 5-[(4-f{2-hydroxy-3-[(methylethyl) propoxy}-4,3a-dihydroimidazolidino[2,1-b]- amino propoxy}phenyl)carbonyl-4 quinazolin-2-one methyl-4-imidazolin-2-one 5 N N 0 0 H-I OHH OH 0 0 OHO ~ ~ 0 -~HN NH NH H 0 (Example 3) (Example 4) 6-[3-(2-{2-hydroxy-3-[(methylethyl)- 5-({4-[3-(2-f{2-hydroxy-3-[(methyethyl amino] propoxy}phenoxy)propoxy]-4,3a- aminopropoxy}phenoxy)propoxy]phenyl}c dihydro- imidazolidino [2,1 -b]quinazolin-2- arbonyl)-4-methyl-4-imidazolin-2-one one 26 WO 2004/050657 PCT/US2003/037812 OH H H ON-NH - N-NH 0/_ N 0 0 (Example 5) (Example 8) N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)- 6-{4-[3-(4-{(2S)-2-hydroxy-3 amino]propoxy}phenoxy)propyl]-2-[2-chloro- [(methylethyl) anino]propoxy} 4-(6-oxo(1,4,5-trihydropyridazin-3- phenoxy)-propoxy]-3-chlorophenyl} yl))phenoxy]acetamide 2,4,5-trihydropyridazin-3-one O" - N O'_ N zH H HH O H M e NO 0 0H H O N O N 5 0 0 (Example 6) (Example 7) N-[3-(4-{(2S)-2-hydroxy-3- N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl) [(methylethyl)-amino]propoxy}- amino] propoxy}phenoxy)propyl]-4-( 2 phenoxy)propyl]-2-[4-(5- cyano-2- oxo(6-hydroquinolyl-oxy))butanamide methyl-6-oxo(3-hydropyridyl) phenoxy]acetamide 27 WO 2004/050657 PCT/US2003/037812 O - N Br 0H H Cl H, H N-NH N 0 0 (Example 9) N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3-bromophenoxy)propyl]-2 5 [2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]acetamide O" - N NC OH H CI H - N-NH 0 10 (Example 10) N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3-cyanophenoxy)propyl]-2 [2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]acetamide ON OH H \ NC O O NC H H-~ N-NH O~ N 0 / 0 15 0 (Example 11) N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2-cyanophenoxy)propyl]-2 [2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]acetamide 28 WO 2004/050657 PCT/US2003/037812 O - N Br ,H H 0- N-NH 5 (Example 12) 6-{4-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3-bromophenoxy)propoxy] -3 -chlorophenyl} -2,4,5-trihydropyridazin-3 -one O'N NC OH H N-NH 10 (Example 13) 2-{ (2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-5-{3-[2-chloro-4-(6-oxo(1,4,5 trihydropyridazin-3-yl))phenoxy]propoxy}benzenecarbonitrile 15 O'- NIt OH H CI Br - N-NH (Example 14) 20 6-{4-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2 bromophenoxy)propoxy]-3-chlorophenyl}-2,4,5-trihydropyridazin-3-one 29 WO 2004/050657 PCT/US2003/037812 NC4 bH OH OH NC O N-NH (Example 15) 5-{(2S)-2-hydroxy-3-[(nethylethyl)amino]propoxy}-2-{3-[2-chloro-4-(6-oxo(1,4,5 5 trihydropyridazin-3-yl))phenoxy]propoxy}benzenecarbonitrile PHARMACEUTICAL COMPOSITIONS This invention further provides a pharmaceutical composition comprising: 10 (i) an effective amount of a compound of the present invention; and (ii) a pharmaceutically-acceptable carrier. In some embodiments, the pharmaceutically-acceptable carrier is chosen from wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, sweeteners, and 15 therapeutic agents other than those compounds of the present invention. In some embodiments, the pharmaceutically-acceptable carrier is chosen from fillers, diluents, excipients, and solvent encapsulating materials. In some embodiments, the pharmaceutically-acceptable carrier is active with respect to the patient. In some embodiments, the pharmaceutically-acceptable carrier are chosen from: (1) sugars, such 20 as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose band its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) tale; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, 25 such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl 30 WO 2004/050657 PCT/US2003/037812 alcohol; (20) pH buffered solutions; and (21) polyesters, polycarbonates and polyanhydrides. In some embodiments, the pharmaceutically-acceptable carrier is liquid and in others it is solid. 5 The inventive pharmaceutical composition may be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (for example, aqueous or non-aqueous solutions or suspensions), tablets, (for example, those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, 10 soft gelatin capsules, mouth sprays, emulsions and microemulsions; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or a sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, 15 as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. METHODS OF USE The present invention further provides a method for regulating calcium 20 homeostasis, comprising administering an effective amount of a compound of the present invention to an animal in need of such regulation. The present invention further provides a method for treating a disease, disorder or condition in which disregulation of calcium homeostasis is implicated, comprising administering an effective amount of a compound of the present invention to an animal in 25 need of such treatment. The present invention also provides a method for treating cardiovascular disease, stroke, epilepsy, an ophthalmic disorder or migraine, comprising administering an effective amount of a compound of the present invention to an animal in need of such treatment. 30 In one embodiment of the present invention, the cardiovascular disease is heart failure, hypertension, SA/AV node disturbance, arrythmia, hypertrophic subaortic 31 WO 2004/050657 PCT/US2003/037812 stenosis or angina. In another embodiment of the inventive method, the heart failure is chronic heart failure or congestive heart failure. The present invention further provides a method of inhibiting P-adrenergic receptors and/or inhibiting phosphodiesterase PDE, including PDE3, comprising 5 administering an effective amount of a compound of the present invention to an animal in need of such treatment. The compound of the present invention may be administered by any means known to an ordinarily skilled artisan. For example, the compound of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, 10 buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, and intraosseous injection and infusion techniques. The exact administration protocol will vary depending upon various factors including the age, body weight, general health, sex and diet of the patient; the 15 determination of specific administration procedures would be routine, The compound of the present invention may be administered by a single dose, multiple discrete doses, or continuous infusion. Pump means, particularly subcutaneous pump means, are useful for continuous infusion. Dose levels on the order of about 0.001 mg/kg/d to about 10,000 mg/kg/d of 20 compound of the present invention are useful for the inventive method, with preferred levels being about 0.1 mg/kg/d to about 1,000 mg/kg/d, and more preferred levels being about 1 mg/kg/d to about 100 mg/kg/d. The specific dose level for any particular patient will vary depending upon a variety of factors, including the activity and the possible toxicity of the specific compound employed; the age, body weight, general health, sex, 25 and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the congestive heart failure, and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art and within the skill of a 30 physician. Any administration regimen well known to an ordinarily skilled artisan for regulating the timing and sequence of drug delivery can be used and repeated as 32 WO 2004/050657 PCT/US2003/037812 necessary to effect treatment in the inventive method. A further regimen may include pretreatment and/or co-administration with additional therapeutic agents. The compound of the present invention can be administered alone or in combination with one or more additional therapeutic agent(s) for simultaneous, separate, 5 or sequential use. The additional agent(s) can be any therapeutic agent(s), including without limitation one or more compound(s) of the present invention. The compound of the present invention can be co-administered with one or more therapeutic agent(s) either (i) together in a single formulation, or (ii) separately in individual formulations designed for optimal release rates of their respective active agent. 10 The compounds of the present invention may be readily made. For example, when m+n is 0 and P and X are directly bonded, the compounds of the present invention may be prepared using standard aromatic chemistry known to those skilled in the art. As shown in general Scheme 1 below, protected aryl hydroxyl precursors of moieties X (P may be e.g., acetyl, benzyl, alkylsilyl, or other appropriate protecting group and Q-T are 15 chosen to reach a particular moiety X) may be deprotected and then may be reacted with epichlorohydrin to yield epoxide intermediates which may be reacted with amines to yield the final products. Furthermore, such a scheme could readily be adapted to link Ar to P or to link Ar to L or to link Ar to X. 20 Scheme 1 P P 0 P PO Q Deprotection HO Q Cl RNH2 T R T R T R NaOH, p-dioxane R OH P RHN O Q T R S 33 WO 2004/050657 PCT/US2003/037812 In cases m is 1, wherein X and P or X and Ar are connected by a linker of one or more atoms, the linker may be attached to P, Ar, or X, and the intermediate moiety P-L or X-L or L-Ar may then be linked to X or Ar/p or /X, respectively, to form A-(Ar)a-L-X. For example, a general method for preparing p-(Ar)n-L may proceed as follows. 5 Protected phenols of the type depicted below in general Scheme 2 may be reacted with suitably protected linker chains L. "J" in the scheme may be any of various species known to those skilled in the art which can be reacted with a hydroxyl group. For example, J may be a bromine atom, which can be displaced by reaction with the anion of the phenol, or J may be an alcohol group which can be reacted with the phenol under 10 Mitsunobu reaction conditions. P' may be a suitable protecting group which can be removed under different condition than those which cleave P. The partially deprotected compound may be reacted with a precursor of moiety X or a precursor of Ar, as described in general Scheme 4, before attaching the remaining P constituent. Such a scheme could be readily adapted to link L to Ar or to link -L to Ar by one of ordinary skill in the art. 15 Scheme 2 OH <L'-Op PO PO" OH LN L-OP' Deprotection PO O,L-'OH Coupling method 20 In addition, a general method for preparation of X-(Ar)n-L is analogous to the method for p-(Ar)n-L may proceed as follows. Precursors of moieties X with a hydroxyl group on one of the rings may be reacted with a protected linker group as described in Scheme 2 above and may be subsequently deprotected. Such a scheme could be readily adapted to link X to Ar or to link X to L-(Ar)a-p or to link X to Ar-p by one of ordinary 25 skill in the art. 34 WO 2004/050657 PCT/US2003/037812 Scheme 3 P P p HO Q J'L OP PO L-O Q Deprotection HOL O Q T R Coupling method T R T R S S S General method for reacting A-L or X-L with X or A to make A-L-X may proceed 5 as follows. A resultant compound from general Scheme 2 may be reacted with an aryl hydroxyl precursor of moiety X via standard Mitsunobu chemistry as shown below in Scheme 4. Following deprotection of the remaining hydroxyl group, sequential reaction with epichlorohydrin and a substituted amine may deliver the final product. 10 Scheme 4 P H O Q 7 p1. Deprotect P T R PO Os 0 2. Epichlorohydrin O'LOH S7 3. RNH 2 T R Coupling method S OH )P RHN O o Q T*R S Indeed, general Schemes 1-4 could be readily adapted to make X-(L)m-(Ar)n-3 by one of ordinary skill in the art. 15 A compound from general Scheme 3 may similarly be reacted with a protected phenol as shown below, and the coupling product may be converted to the final compound by the same deprotection/reaction with epichlorohydrin/reaction with RNIH 2 sequence as previously described. 35 WO 2004/050657 PCT/US2003/037812 OH pH P 1. Deprotect HO O P 2. Epichlorohydrin 1-0 Q~ PO 01Q 3. RNH 2 T Coupling method T R S S OH P RHN O ,'L 0 Q T R S EXAMPLES 5 Example 1: 6-{2-hydroxy-3-[(methylethyl)amino]propoxy}-4,3a-dihydroimidazolidino [2,1-b]quinazolin-2-one is synthesized according to the method of Scheme I. Scheme I HNY>?OEt 1. H2N O , NaOAc, EtOH AcO CHO 2. NaCNBH 3 AcO
NO
2 3. H 2 , Pd/C N H 4. CNBr 5. Et 3 N 0 ~ N NC0 HO O C O__O__O__iPrNH2 H N N NaOH, p-dioxane H OH HN_,, ON OO S N H 10 36 WO 2004/050657 PCT/US2003/037812 2-oxo-4,3a-dihydroimidazolidino[2,1-b]quinazolin-6-yl acetate: 3-formyl-4-nitrophenyl acetate (10 mmol) is added to a solution prepared from glycine ethyl ester hydrochloride (3.0g, 24 mmol) and anhydrous sodium acetate (820 mg, 10 mmol) in methanol (80 mL). After stirring the thick mixture for 15 minutes, sodium cyanoborohydride (380 mg, 6 5 mmol) is added, resulting in dissolution of the precipitate. After stirring for an hour, the solvent is evaporated and the residue is partitioned between ethyl acetate (50 mL) and saturated aqueous NaHCO 3 (50 mL). The layers are separated and the aqueous phase is extracted with additional ethyl acetate. The combined organic fractions are washed with saturated aqueous NaHCO 3 and brine, dried over magnesium sulfate, and concentrated in 10 vacuo. The crude residue is purified by silica gel chromatography to furnish the benzylamine intermediate, which is dissolved in 20 mL of ethanol and hydrogenated at 60 psi over 10% Pd-C overnight. After removing the catalyst by filtration, a solution of cyanogen bromide (760 mg; 7.1 mmol) in 5 mL of ethanol is added to the filtrate. After stirring overnight, the mixture is treated with triethylamine (1.1 mL, 7.8 mmol) and 15 stirring is continued overnight again. The formed precipitate is collected by filtration, washed repeatedly with water and ethanol-ether, and dried to provide the title compound. 6-hydroxy-4,3a-dihydroimidazolidinoF2,1-blquinazolin-2-one: The above compound is suspended in 10 mL of methanol and treated with 2 mL of a 2.5 M solution of NaOH. 20 After stirring for 1 hour, the precipitate is collected by filtration, washed with acetone, and dried under vacuum to furnish the phenol as a solid. 6-(oxiran-2-vlmethoxy)-4,3a-dihydroimidazolidino[2,1-blquinazolin-2-one: 6-Hydroxy 4,3a-dihydroimidazolidino[2,1-b]quinazolin-2-one (3.8 mmol) is added to a solution of 25 NaOH (150 mg; 3.8 mmol) in 5 mL of H 2 0. Epichlorohydrin (2.5 mL, 32 mmol) andp dioxane are added, and the reaction is stirred for 24 hours under inert atmosphere. The reaction mixture is extracted with methylene chloride, and the organic phase is washed with brine and water, dried, and concentrated to deliver the crude product as a brown oil. The crude material is purified on a silica gel column eluting with 25% hexane in ethyl 30 acetate to deliver the pure product as a solid. 37 WO 2004/050657 PCT/US2003/037812 6-{2-hydroxy-3-[(methylethyl)aminolpropoxyl-4,3a-dihydroimidazolidino [2,1 blquinazolin-2-one: The epoxide above (2.7 mmol) and isopropylamine (3.8 mmol) are dissolved in methanol (5 mL) and stirred together for 36 hrs. The solvent is removed under vacuum and the crude residue is applied to a silica gel column, eluting with 5% 5 methanol in CH 2 Cl 2 , to deliver the compound of example 1. Example 2: 5-[(4-{2-hydroxy-3-[(methylethyl)amino]propoxy}phenyl)carbonyl]-4 methyl- 4-imidazolin-2-one is synthesized according to the method of Scheme II. 10 Scheme II (Z) O COOH COCI HN YNH 0 z) 0 - H 2 /EtOH/Pd-C HN NH o
AIC
3 0 0 0 0 ~ 0 HO-O (Z) iPrNH2 HN NHHN NH HN.NH NaOH, p-dioxane O 0 OH 0 H HN NH 2 0 4-methyl-5-fr4-(phenylmethoxylphenyllcarbonyl}-4-imidazolin-2-one: The potassium salt of 4-(phenylmethoxy)benzoic acid (56 mmol) is suspended in 150 mL of CH 2 Cl 2 , 15 cooled in an ice-bath, and treated with 7.50 g (60 mmol) of oxalyl chloride added dropwise. Following the completion of the addition, the mixture is refluxed for 30 minutes, cooled, and filtered. The filtrate was added dropwise to a stirred mixture of 4 38 WO 2004/050657 PCT/US2003/037812 methyl-4-imidazolin-2-one (56 mmol, prepared by the method of Duschinsky and Dolan, J. Am. Chem. Soc. 1945, 67, 2079) and anhydrous aluminum chloride (112 mmol) in 50 mL of nitrobenzene. The resulting mixture is stirred at 65 'C for 6 hours and then poured over ice. The precipitate formed is collected by filtration, washed with ether and water, 5 and recrystallized from ethanol/water to deliver the product. 5-[(4-hydroxyphenvl)carbonyll-4-methyl-4-imidazolin-2-one: The benzyl protected compound (15 mmol) is dissolved in ethanol, treated with a catalytic amount of 10% palladium on carbon, and hydrogenated at 50 psi overnight. The catalyst is removed by 10 filtration and the solvent was removed in vacuo to yield the crude product as an oil, which is used directly for the next step. 4-methyl-5-{r4-(oxiran-2-vlmethoxv)phenvllcarbonyl}-4-imidazolin-2-one: The phenol (3.5 mmol) is added to a solution of NaOH (150 mg; 3.8 mmol) in 5 mL of H 2 0. 15 Epichlorohydrin (2.5 mL, 32 mmol) and p-dioxane are added, and the reaction is stirred for 24 hours under inert atmosphere. The reaction mixture is extracted with methylene chloride, and the organic phase is washed with brine and water, dried, and concentrated to deliver the crude product as an oil. The crude material is purified on a silica gel column eluting with 20% hexane in ethyl acetate to deliver the pure product. 20 5-[(4-{2-hydroxy-2-[(methylethyl)aminolethoxv}phenvllcarbonyll-4-methyl-4 imidazolin-2-one: The epoxide above (2 mmol) and isopropylamine (4 mmol) are dissolved in methanol (5 mL) and stirred together for 36 hrs. The solvent is removed under vacuum and the crude residue is applied to a silica gel column, eluting with 10% 25 methanol in CH 2
CI
2 , to deliver the compound of example 2. Example 3: 6-[3-(2-{2-hydroxy-3-[(methylethyl)amino] propoxy}phenoxy)propoxy 4,3a-dihydro- imidazolidino[2,1-b]quinazolin-2-one is prepared according to the method of Scheme III. 30 39 WO 2004/050657 PCT/US2003/037812 Scheme III
OCH
2 Ph OCH 2 Ph OCH 2 Ph OH Br' -- OTHP O- OTHP OH HO C 1. Deprotect 0 OCH 2 Ph 2. Epichlorohydrin N N O O ~ N3. iPrNH 2 H _N O Mitsunobu conditions H N O H O ' N N 3 H 5 1-(3-perhydro-2H-pyran-2-yloxypropoxy)-2-(phenylmethoxylbenzene: Sodium hydride (10 mmol) is added to a solution of 2-(phenylmethoxy)phenol (9 mmol) in 50 mL of dry ether, and subsequently treated with 12 mmol of 3-bromo-1-perhydro-2H-pyran-2 yloxypropane in 10 mL of ether. The mixture is stirred at 70 'C for 5 hours, then quenched by the addition of 2 mL of methanol followed by partitioning between ethyl 10 acetate and water. The organic phase is washed with brine, dried, concentrated, and the crude residue is purified on a silica gel column, eluting with 5% ethyl acetate in hexane, to obtain the product as a clear oil. 3-r2-(phenylmethoxylphenoxylpropan-1-ol: The tetrahydropyranyl-protected alcohol (10 15 mmol) is dissolved in methylene chloride (20 mL) and treated with 2 mmol of para toluenesulfonic acid. After stirring at room temperature overnight, the reaction mixture is partitioned between methylene chloride and brine, concentrated, and the crude residue is purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain the product as a clear oil. 20 40 WO 2004/050657 PCT/US2003/037812 6-{3-[2-(phenylmethoxyphenoxylpropoxy}-4,3a-dihydroimidazolidino[2,1-blquinazolin 2-one: A mixture of 3-[2-(phenylmethoxy)phenoxy]propan-1-ol and 6-hydroxy-4,3a dihydroimidazolidino[2,1-b]quinazolin-2-one (prepared as in Scheme I) are coupled using diethyl azodicarboxylate and triethylphosphine according to the method of Mitsunobu 5 (Bull. Chein. Soc. Jpn., 1979, 52, 1191-1196). 6-[3-(2-hydroxyphenoxv)propoxyl-4,3a-dihydroimidazolidino[2,1-blquinazolin-2-one: The benzyl protected compound (11 mmol) is dissolved in ethanol, treated with a catalytic amount of 10% palladium on carbon, and hydrogenated at 50 psi overnight. The 10 catalyst is removed by filtration and the solvent was removed in vacuo to yield the crude product as an oil, which is used directly for the next step. 6-{3-[2-(cyclopropylmethoxy)phenoxylpropoxv}-4,3a-dihydroimidazolidinor2,1 blquinazolin-2-one: The phenol (4 mmol) is added to a solution of NaOH (150 mg; 4.4 15 mmol) in 5 mL of H 2 0. Epichlorohydrin (2.8 mL, 35 mmol) and p-dioxane are added, and the reaction is stirred for 24 hours under inert atmosphere. The reaction mixture is extracted with methylene chloride, and the organic phase is washed with brine and water, dried, and concentrated to deliver the crude product as an oil. The crude material is purified on a silica gel column eluting with 20% hexane in ethyl acetate to deliver the 20 pure product. 6-[3-(2-{2-hydroxy-3-r(methylethyllamino propoxy}phenoxy)propoxyl-4,3a-dihydro imidazolidinor2,1-b]quinazolin-2-one: The epoxide above (2.2 mmol) and isopropylamine (4.4 mmol) are dissolved in methanol (5 mL) and stirred together for 36 25 hrs. The solvent is removed under vacuum and the crude residue is applied to a silica gel column, eluting with 10% methanol in CH 2 Cl 2 , to deliver the compound of example 3. Example 4: 5-({4-[3-(2-{2-hydroxy-3-[(methylethyl)amino]propoxy}phenoxy)propoxy] phenyl}carbonyl)-4-methyl-4-imidazolin-2-one is prepared according to the method of 30 Scheme IV. 41 WO 2004/050657 PCT/US2003/037812 Scheme IV HO/ 0 - OCH 2 Ph
OCH
2 Ph HN NH HN NH 0 1. Deprotect 2. Epichlorohydrin N 0 3. iPrNH 2 H HN NH 0 4-methyl-5-[(4-{3-r2-(phenylmethoxy)phenoxy]propoxylphenylcarbonyll-4-imidazolin 5 2-one: 3-[2-(phenylmethoxy)phenoxy]propan-1-ol () and 5-[(4-hydroxyphenyl) carbonyl]-4-methyl-4-imidazolin-2-one are coupled using diethyl azodicarboxylate and triethylphosphine according to the method of Mitsunobu (Bull. Chen. Soc. Jpn., 1979, 52, 1191-1196). 10 5-( 4-[3-(2-{ 2-hydroxy-3-[(methylethyl)aminolpropoxyphenoxy)propoxyl phenyllcarbonyl)-4-methyl-4-imidazolin-2-one (4) is prepared from the product of the previous step by the same sequence of reactions (deprotection, reaction with epichlorohydrin, and subsequent reaction of the epoxide with isopropylamine sequence as described in the previous schemes, as described in Scheme III, to yield the compound of 15 Example 4. Example 5: N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}phenoxy)propyl] 2-[2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]acetamide was prepared according to the method of Scheme V. 20 42 WO 2004/050657 PCT/US2003/037812 Scheme V OBn 1. NaH, DMF OBn
H
2 /Pd-C, EtOH OH 2.N Br,,,-_N O 0 OH 1. NaH, DMF 1. iPrNH 2 (10 eq.), EtOH, 0 0O "116 reflux, 1.5 h 2. O 2. 40% aq. MeNH 2 , r.t., 2N O'\ ' o overnight O0 2 N 0, IO N O 3. 4N HCI in Et 2 O, THF 0 H HO x N OH H O-X 5H H O H O NH2 HCI EtN HOAt, EDC H
CH
2
CI
2 o 0 5 X = PDE3 inhibitory moiety 2-F3-(4-Hydroxy-phenoxy)-propyll-isoindole-1,3-dione: To a stirred solution of 2-[3-(4 benzyloxy-phenoxy)-propyl]-isoindole-1,3-dione (1.25 g, 3.23 mmol) in ethanol / ethyl 10 acetate (2:1) (60 mL) was added palladium on activated carbon (10 wt% Pd, wet Degussa type with 50 wt% water, 315 mg, 0.148 mmol). The reaction mixture was stirred under an atmosphere of hydrogen (1.5 atm) for 16 hours at ambient temperature and then filtered through a pad of Celite*. The filtrate was evaporated to dryness and the residue was purified by flash chromatography over silica gel (50 g) using dichloromethane / 15 methanol (99:1) as eluent. Fractions with Rf= 0.33 (DCM/MeOH 98:2) were combined and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate to give 2-[3-(4-hydroxy-phenoxy)-propyl]-isoindole-1,3-dione as colorless plates 43 WO 2004/050657 PCT/US2003/037812 (730 mg, 76 % yield, 99 % pure by LC-MS and 'H-NMR). 'H NMR (400 MHz; CDCl 3 ): 6 8.13 (in, 2H); 7.69 (in, 2H); 6.62-6.60 (in, 4H); 3.94 (in, 2H); 3.63 (in, 2H); 2.04 (in, 2H). 5 2-[3-(4-Oxiranylmethoxv-phenoxv)-propyll-isoindole-1,3-dione: To a stirred suspension of sodium hydride (60 % dispersion in mineral oil, 108 mg, 2.70 mmol) in NN dimethylformamide (6 mL) under nitrogen at 0 C was added 2-[3-(4-hydroxy-phenoxy) propyl]-isoindole-1,3-dione (730 mg, 2.45 mmol) and the reaction mixture was stirred for 20 minutes at ambient temperature. A solution of 3-nitro-benzenesulfonic acid oxiranyl 10 methyl ester (700 mg, 2.70 mmol) in N,N-dimethylformamide (6 mL) was added at 0 C. The mixture was stirred at ambient temperature for 16 hours, then poured onto a mixture of ice and saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (4 x 25 mL). The combined organic extracts were washed with saturated brine (2 x 25 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue 15 was dissolved in dichloromethane, adsorbed onto silica, evaporated to dryness and the residue dry-loaded onto a silica gel column (50 g). Purification by column chromatography was carried out using a gradient of neat dichloromethane to dichloromethane / ethyl acetate (9:1) as eluent. Fractions with Rf = 0.54 (DCM) were combined and evaporated to dryness under reduced pressure to give 2-[3-(4 20 oxiranylmethoxy-phenoxy)-propyl]-isoindole-1,3-dione as a colorless solid (460 mg, 53 % yield, 95 % pure by LC-MS and 'H-NMR). '1H NMR (400 MHz; CDCl 3 ): 6 8.13 (in, 2H); 7.69 (in, 2H); 6.66 (in, 4H); 4.07 (in, 2H); 3.94 (in, 1H); 3.63 (in, 2H); 3.04 (in, 1H); 2.50 (in, 2H); 2.04 (in, 2H). 25 1-[4-(3-Amino-propoxy)-phenoxyl-3-isopropylamino-propan- 2 -ol via 2-{3-[4-(2 Hydroxy-3-isopropylamino-propoxy)-phenoxyl-propyl}-isoindole-1,3-dione: To a stirred solution of 2-[3-(4-oxiranylmethoxy-phenoxy)-propyl]-isoindole-1,3-dione (460 mg, 1.30 mmol) in ethanol (20 mL) was added iso-propylamine (1.11 mL, 13.0 mmol). The reaction mixture was heated to reflux, then stirred at this temperature for 3 hours, and 30 then concentrated under reduced pressure to give crude 2-{3-[4-(2-hydroxy-3 isopropylamino-propoxy)-phenoxy]-propyl}-isoindole-1,3-dione. The residue was 44 WO 2004/050657 PCT/US2003/037812 dissolved in methylamine (40 wt% in water, 20 mL), stirred at ambient temperature for 16 hours, then diluted with H 2 0 (20 mL) and brine (20 mL), and extracted with dichloromethane (4 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure to give crude 1-[4-(3 5 amino-propoxy)-phenoxy]-3-isopropylamino-propai- 2 -ol as light yellow oil (355 mg, 96 % yield, 90 % pure by LC-MS and 'H-NMR), which was used without further purification. 1H NMR (400 MHz; CDCl 3 ): 8 6.68 (in, 4H); 4.09 (in, 2H); 3.96 (in, 1H); 3.94 (in, 2H); 2.97 (in, 1H); 2.70 (in, 2H); 2.65 (in, 2H); 1.97 (in, 2H); 1.05 (d, 6H total). 10 2-[2-Chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxyl-N-{3-r4-(2-hydroxy-3 isopropylamino-propoxylphenoxylpropyl}acetamide: To a stirred solution of [2-chloro 4-(6-oxo- 1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy] -acetic acid (126 mg, 0.446 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC.HC1, 85.4 mg, 0.446 mmol) and 7-hydroxyazabenzotriazole (HOAt, 60.7 mg, 0.446 mmol) in NN 15 dimethylformamide (4 mL) under N 2 was added a solution of crude 1-[4-(3-amino propoxy)-phenoxy]-3-isopropylamino-propan- 2 -ol (140 mg, 0.496 mmol) in NN dimethylformamide (2 mL), and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was poured into saturated brine (40 mL), made strongly alkaline (pH 11-12) with aqueous sodium hydroxide solution (2 N), and extracted with 20 ethyl acetate (4 x 20 mL), The combined organic layers were washed with saturated brine (2 x 20 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue was dry-loaded and purified by column chromatography on silica gel (4 g) using dichloromethane / methanol (9:1) as eluent. Fractions with Rf = 0.04 were combined and evaporated to dryness under reduced pressure to give 2-[2-chloro-4-(6-oxo-1,4,5,6 25 tetrahydro-pyridazin-3-yl)-phenoxy]-N-{3-[4-(2-hydroxy-3-isopropylaminopropoxy) phenoxy]propyl}acetamide as an off-white solid (136 mg, 56 % yield, 97 % pure by LC MS and 'H-NMR). 'H NMR (400 MHz; CDCl 3 ): 8 7.51 (d, 1H); 7.41 (dd, 1H); 6.69 (dd, 1H); 6.66 (in, 4H total); 4.83 (s, 2H); 4.09 (d, 1H); 3.96 (in, 1H); 3.94 (in, 2H); 3.20 (in, 2H); 2.97 (dq, 1H); 2.70 (in, 1H); 2.21 (in, 2H); 1.97 (in, 2H); 1.62 (in, 2H); 1.05 (d, 6H 30 total). 45 WO 2004/050657 PCT/US2003/037812 The required PDE3 inhibitor fragment, [2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin 3-yl)-phenoxy]-acetic acid, was synthesized as described in Scheme V-a: Scheme V-a 5 OH Br OEt OEt O C 0 OEt 0 0 00 C1 CI__ 0_ _ _ 10_ _ _ _ _
K
2
CO
3 , acetone, reflux A1C1 3 , CH 2
CI
2 00 O Et O OH OH
H
2
NNH
2 C NaOH C EtOH EtOH N N NH NH 0 0 Ethyl 2-chlorophenoxyacetate: To a stirred solution of 2-chlorophenol (20.0 g, 156 10 mmol) in acetone (300 mL) under nitrogen at ambient temperature were added potassium carbonate (23.7 g, 171 mmol) and ethyl bromoacetate (7, 26.0 g, 156 mmol). The reaction mixture was then heated to reflux and stirred at this temperature under nitrogen for 7 hours. After cooling to ambient temperature, the reaction mixture was filtered to remove insolubles. The filtrate was then concentrated under reduced pressure to give the 15 product as highly viscous, light yellow oil (32.0 g, 95% yield, 95% pure by LCMS and IH NMR), 'H NMR (400 MHz; CDCl 3 ): 5 7.16 (m, 1H); 7.03 (in, 1H); 6.76 (in, 1H); 6.71 (m, 1H); 4.90 (s, 2H); 4.12 (q, 2H); 1.33 (t, 3H). 4-[3-Chloro-4-(ethoxycarbonylmethoxy)phenyll-4-oxobutyric acid: To a stirred solution 20 of ethyl 2-chlorophenoxyacetate (32.0 g, 149 mmol) in dichloromethane (75 mL) at ambient temperature under nitrogen was added succinic anhydride (22.4 g, 224 mmol). The reaction mixture was cooled in ice-water and to this was added portion wise aluminum trichloride (59.6 g, 447 mmol), whilst maintaining the temperature below 20 'C. The reaction mixture was then allowed to stir at ambient temperature for 20 46 WO 2004/050657 PCT/US2003/037812 minutes and was then heated to reflux and stirred at this temperature for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then poured into a mixture of ice, water (200 ml) and HCl (10 N, 100 ml). The two phase system was separated and the aqueous layer was extracted with ethyl acetate (5 x 100 mL). All organic layers were 5 then combined and washed with water (2 x 100 mL), dried over Na 2 S 04, and concentrated under reduced pressure to give an orange oily solid. Hexane (300 mL) was added, and after standing at ambient temperature for 1 hour, the precipitate was filtered off and re-crystallized from ethyl acetate / hexane to give the diketo compound as a light yellow powder (21.5 g, 46 % yield, 98 % pure by LCMS and 'H NMR), 'H NMR (400 10 MHz; CDCl 3 ): 8 7.79 (in, 1H); 7.66 (in, 1H); 6.79 (in, 1H); 4.90 (s, 2H); 4.12 (q, 2H); 2.82 (in, 2H); 2.42 (in, 2H); 1.30 (t, 3H). 6-[3-Chloro-4-(ethoxycarbonylmethoxy)phenyll-4,5-dihydro-3(2H)-pyridfizinone: To a stirred suspension of 4-[3-chloro-4-(ethoxycarbonylmethoxy)phenyl]-4-oxobutyric acid 15 (21.5 g, 69.2 mmol) in ethanol (200 mL) at 0 *C was added a solution of hydrazine monohydrate (3.4 mL, 69.2 mmol) in ethanol (20 mL). The reaction mixture was then allowed to warm to ambient temperature and stirred at this temperature for 15 minutes before being heated to reflux and stirred at this temperature for 3 hours. Ethyl acetate (40 mL) was added to the hot solution and the mixture was allowed to cool to ambient 20 temperature. The precipitate which formed was filtered off and washed with water (2 x 100 mL) and cold ethanol (2 x 100 mL), then dried with suction, then under high vacuum to give the pyridazinone as light yellow powder (17.6 g, 82 % yield, 99 % pure by LCMS and 'H NMR), 1H NMR (400 MHz; CDCl3): 8 7.52 (in, 1H); 7.41 (in, 1H); 6.70 (in, iH); 4.90 (s, 2H); 4.12 (q, 2H); 2.22 (m, 2H); 1.62 (in, 2H); 1.30 (q, 3H). 25 Pyridazinone carboxylic acid (6-{4-r3-carboxymethoxyl-3-chlorophenyl}-4,5-dihydro 3(2H)-pyridazinone): To a stirred suspension of 6-[3-chloro-4-(ethoxycarbonyl methoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (17.6 g, 56.6 mmol) in ethanol (150 mL) at ambient temperature were added water (150 mL) and sodium hydroxide (9.10 g, 30 227 mmol). The reaction mixture was then heated to 80 C and stirred at this temperature for 2.5 hours. The solution was allowed to cool until precipitation occurred, then the 47 WO 2004/050657 PCT/US2003/037812 suspension was acidified to pH 1-2 with HCI (2 N, 100 mL) with stirring. After standing at ambient temperature for 1 hour, the precipitate was filtered off and washed with water (2 x 100 mL) and ethanol (2 x 100 mL). The solid was dried under high vacuum at 45 'C to give 6-{4-[3-carboxymethoxy]-3-chlorophenyl}-4,5-dihydro-3(2H)-pyridazinone as a 5 light yellow powder (13.4 g, 84 % yield, 99 % pure by LCMS and 'H NMR), 'H NMR (400 MHz; CDCl 3 ): 8 7.52 (in, 1H); 7.44 (in, 1H); 6.72 (in, 1H); 4.88 (s, 2H); 2.21 (in, 2H); 1.61 (in, 2H). Using the procedure of Scheme V-a, different halo alkanoic acids may be utilized to 10 obtain PDE inhibitor fragments with varying chain lengths. Example 6: 2-[4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenoxy]-N-{3
[
4
-(
2 -hydroxy-3-isopropylaminopropoxy)phenoxy]propyl}acetamide was synthesized using the same procedure as was used for Example 5, starting from [4-(5-cyano-2-methyl 15 6-oxo-1,6-dihydro-pyridin-3-yl)-phenoxy]-acetic acid (127 ig, 0.446 mmol). 2-[4-(5 Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenoxy]-N- {3-[4-(2-hydroxy-3-iso propylamino-propoxy)-phenoxy]-propyl)-acetamide (Example 6) was isolated as off white solid (95 mg, 39 % yield, 93 % pure by LC-MS and 'H-NMR). 'H NMR (400 MHz; CDCl 3 ): 8 7.70 (s, 1H); 7.19 (in, 2H); 6.72 (in, 2H); 6.66 (in, 4H); 4.83 (s, 2H); 20 4.09 (in, 2H); 3.96 (in, 1H); 3.94 (in, 2H); 3.20 (in, 2H); 2.97 (in, 1-I); 1.71 (s, 3H); 1.05 (d, 6H total). The required PDE3 inhibitor fragment, 2-[4-(5-cyano-2-methyl-6-oxo-3-hydropyridyl) phenoxy]acetic acid, was prepared according to Scheme V-b. 25 48 WO 2004/050657 PCT/US2003/037812 Scheme V-b OMe OMe MeO O o MeO MeO NI H 2 Nt e 0N NH DMF, 85C, 18 hr NaOMe, DMF 0 950C, 18 hr CN BBr, 3 eq., CH 2
C
2 HO 1. NaH (2 eq.), DMF, room temp. 0 EtO Br (12eq)N room temp., 6 hr .. H 2. Br QOEt (1.2 eq.) NH CN DMF, 80 0 C, 45 min CN 0 LiOH (4 eq.) HO "N EtOH/H 2 0 (1:1), room NH temp., 1 hr CN 5 4-Dimethylamino-3-(4-methoxy-phenyl)-but-3-en-2-one: To a stirred solution of 1-(4 methoxy-phenyl)-propan-2-one (8.37 g, 51.0 mmol) in NN-dimethylformamide (200 mL) was added dimethoxymethyl-dimethyl-amine (27 mL, 203 mmol). The reaction mixture was then stirred for 18 hours at 85 'C, allowed to cool to ambient temperature and excess 10 solvent and reagents were removed under reduced pressure to give crude 4 dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one as yellow oil which was used in the following step without further purification. 5-(4-Methoxy-phenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile: To a stirred 15 solution of sodium hydride (60% dispersion in mineral oil, 4.5 g, 112 mmol) in NN dimethylformamide (100 mL) was added dropwise at 0 'C a solution of crude 4 dimethylamino-3-(4-methoxyphenyl)-but-3-en-2-one from the previous step, 2-cyano acetamide (4.75 g, 56.5 mmol) and methanol (4.54 mL, 112 mmol) in N,N dimethylformamide (50 mL). The reaction mixture was stirred at ambient temperature 20 for 15 minutes and then at 95 'C for 18 hours. After cooling to ambient temperature most 49 WO 2004/050657 PCT/US2003/037812 of the solvent was removed under reduced pressure. The residue was hydrolysed with saturated aqueous ammonium chloride solution (100 mL). The precipitated solid was collected by filtration with suction, rinsed with water and diethyl ether, and dried under vacuum to give 5-(4-methoxy-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3 5 carbonitrile as a brownish solid (10.0 g, 82 % yield over two steps, 99 % pure by LC-MS and 'H NMR), 1H NMR (400 MHz; CDC1 3 ): 8 7.70 (s, 1H); 7.19 (in, 2H); 6.72 (in, 2H); 3.73 (s, 3H); 1.71 (s, 3H). 5-(4-Hydroxy-phenyll-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile: To a stirred 10 solution of 5-(4-Methoxy-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (10.0 g, 41.6 mmol) in dichloromethane (200 mL) was added dropwise at 0 0 C a solution of boron tribromide (11.8 mL, 125 mmol) in.DCM (125 mL). The reaction mixture was stirred for 6 hours at ambient temperature, poured into a mixture of ice and saturated ammonium chloride solution (100 mL), and stirred for 1 hour at room temperature. The 15 formed precipitate was filtered off, rinsed with water and re-dissolved in aqueous sodium hydroxide (2 N, 400 mL). The aqueous solution was washed with ethyl acetate (100 mL), acidified to pH 4 with aqueous hydrochloric acid (2 N), and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (2 x 200 mL), dried (MgSO 4 ) and evaporated to dryness to give 5-(4-hydroxy-phenyl)-6-methyl-2-oxo-1,2 20 dihydro-pyridine-3-carbonitrile as a yellow solid (3.25 g, 46 % yield, 92 % pure by LC MS and 'H NMR), 1 H NMR (400 MHz; CDCl 3 ): 6 7.70 (s, 1H); 7.13 (in, 2H); 6.68 (in, 2H); 1.71 (s, 3H). [4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)phenoxy] -acetic acid ethyl ester: 25 To a stirred suspension of sodium hydride (60 % dispersion in mineral oil, 1.16 g, 29.0 mmol) in NN-dimethylformamide (50 mL), was added at 0 'C a solution of 5-(4 hydroxy-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (3.25 g, 14.4 mmol) in NN-dimethylformamide (50 mL). The mixture was stirred at ambient temperature for 30 minutes. A solution of ethyl 2-bromoacetate (2.0 mL, 18.0 mmol) in NN 30 dimethylfornamide (10 mL) was added at 0 'C, the mixture was stirred for 30 minutes at 0 'C, for 30 minutes at ambient temperature, and then for 45 minutes at 80 'C. The 50 WO 2004/050657 PCT/US2003/037812 mixture was allowed to cool to room temperature, concentrated in vacuo and re-dissolved in ethyl acetate (300 mL). The solution was extracted with water (3 x 150 mL). The combined aqueous layers were acidified to pH 2 with aqueous hydrochloric acid (1 N) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried 5 (MgSO 4 ) and evaporated to dryness. The residue was purified by column chromatography on silica gel (50 g) using 2 % methanol in dichloromethane as eluent to give [4-(5-Cyano-2-methyl-6-oxo- 1,6-dihydro-pyridin-3-yl)phenoxy] -acetic acid ethyl ester as light yellow powder (1.3 g, 29 % yield, 80-90 % pure by LC-MS and 'H NMR), 1 H NMR (400 MHz; CDCl 3 ): 5 7.70 (d, 1H); 7.19 (in, 2H); 6.72 (in, 2H); 4.90 (s, 2H); 10 4.12 (q, 2H); 1.71 (s, 3H); 1.30 (t, 3H). [4-(5-Cyano-2-methyl-6-oxo- 1,6-dihydro-pyridin-3 -yl)-phenoxy] -acetic acid: To a stirred solution of [4-(5-Cyano-2-methyl-6-oxo- 1,6-dihydro-pyridin-3 -yl)phenoxy] -acetic acid ethyl ester (1.3 g, 4.16 mmol) in a mixture of 1,4-dioxane (25 mL) and water (25 15 mL) was added lithium hydroxide mono hydrate (700 mg, 16.7 mmol). The reaction mixture was stirred for 2 hours at ambient temperature, diluted with water (50 mL), washed with diethylether (2 x 25 mL), cooled to 0 *C and acidified to pH 2 with aqueous hydrochloric acid (5 N). After standing at ambient temperature overnight the formed precipitate was filtered off with suction, washed with water and dried under vacuum to 20 give [4-(5-cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenoxy] -acetic acid as a light yellow crystalline solid (758 mg, 64 % yield, 97 % pure by LC-MS and 1 H NMR), 1 H NMR (400 MHz; CDCl 3 ): 8 7.70 (d, 1H); 7.20 (in, 2H); 6.73 (in, 2H); 4.88 (s, 2H); 1.71 (s, 3H). 25 Example 7: N-{3-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenoxy]-propyl}-4-(2-oxo 1,2-dihydro-quinolin-6-yloxy)butyramide was synthesized using the same procedure as was used for Example 5, starting from 4-(2-oxo-1,2-dihydro-quinolin-6-yloxy)-butyric acid (110 mg, 0.446 mmol). N-{3-[4-(2-Hydroxy-3-isopropylanino-propoxy)-phenoxy] propyl}-4-(2-oxo-1,2-dihydro-quinolin-6-yloxy)-butyramide was isolated as an off-white 30 solid (103 mg, 45 % yield, 97 % pure by LC-MS and 1 H-NMR). 'HNMR (400 MHz; CDCl 3 ): 6 7.48 (m, 1H); 7.36 (d, 1H); 6.79 (in, 1H); 6.66 (in, 4H); 6.63 (in, 1H); 6.57 (d, 51 WO 2004/050657 PCT/US2003/037812 1H); 4.09 (s, 2H); 3.96 (in, 1H); 3.94 (in, 4H total); 3.20 (in, 2H); 2.97 (in, 111); 2.70 (m, 2H); 2.18 (in, 2H); 1.99 (in, 2H); 1.97 (in, 2H); 1.05 (d, 6H total). The required PDE3 inhibitor fragment, 4-(2-oxo-1,2-dihydro-quinolin-6-yloxy)-butyric 5 acid, was synthesized as described in Scheme V-c. Scheme V-c HOIO EtO OH E 0 EtO I N DBU/PrOH NO H irH 20% HCI O HO O N 0 H 10 Methyl 4-(2-oxo-6-hydroquinolyloxy)butanoate: Methyl 4-bromobutyrate (6.8 g) was added drop-wise with stirring to a solution of 5 g of 6-hydroxyhydroqionoline-2-one and 7 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 75 mL of isopropanol, and refluxed for 4 hours. After cooling and removal of the solvent under vacuum, the residue was 15 dissolved in methylene chloride and the organic phase was washed successively with 0.5 N NaOH, diluted HCl and water, dried over MgS04, and concentrated. Recrystallization of the crude product from water furnished the substituted quinolone as colorless needles, 1H NMR (400 MHz; CDCl 3 ): 8 7.48 (in, 1H); 7.36 (d, 1H); 6.79 (in, 1H); 6.63 (in, lH); 6.57 (d, 1H); 3.94 (in, 2H); 3.67 (s, 3H); 2.25 (in, 2H); 2.10 (m, 2H). 20 4-(2-oxo-6-hydroquinolyllbutyric acid: A suspension of the methyl ester in 20% HCl was stirred for 2 hours at 90 'C, cooled, and the crystals were collected by filtration, washed with cold water, and dried to deliver the acid as a granular solid, IH NMR (400 MHz; CDCl 3 ): 3 7.48 (in, 1H); 7.36 (d, 11-); 6.79 (in, 1H); 6.63 (in, 1H); 6.57 (d, 1H); 3.94 (in, 2H); 2.23 (in, 2H); 1.98 (in, 2H). 52 WO 2004/050657 PCT/US2003/037812 Example 8: 6-(3-Chloro-4-{3-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenoxy] propoxy} -phenyl)-4,5-dihydro-2H-pyridazin-3-one was synthesized according to Scheme VI. 5 Scheme VI OH N-NH OH OAc OAc O Ac 2 0 H 2 /Pd-C Cl pyridine, CH 2 Cl 2 EtOH Polymer supported PPh 3 (2 eq) OBn OBn OH DIAD (1.4 eq.), CH 2
CI
2 02N' OAc OH O LiOH, dioxane/H 2 0 NaH, DMF, r.t. 18 hr CI NH CI NH iPrNH 2 N OH N-NH EtOH N O~-O \/O O O Cl 10 Acetic acid 4-hydroxy-phenyl ester: To a stirred solution of 4-benzyloxy-phenol (4.0 g, 20.0 mmol) in tetrahydrofuran (50 mL) was added pyridine (1.94 ml, 24.0 mmol) and acetic anhydride (2.26 mL, 24.0 mmol). The reaction mixture was heated to reflux and stirred at this temperature for 2 hours, cooled to ambient temperature then poured into ethyl acetate (200 mL). The resultant solution was washed with aqueous hydrochloric 53 WO 2004/050657 PCT/US2003/037812 acid (0.5 N, 2 x 50 mL), aqueous sodium carbonate solution (2 N, 2 x 50 mL) and saturated brine (2 x 50 mL). The organic layer was dried (Na 2 S04) and concentrated under reduced pressure to give crude acetic acid 4-benzyloxy-phenyl ester. This product was dissolved in ethanol / tetrahydrofuran (5:1) (300 mL) under nitrogen and to the 5 solution was added palladium on carbon (10 wt% palladium, 50 % wet Degussa type, 1.80 g, 0.85 mmol). The reaction mixture was stirred at ambient temperature for 2 hours under hydrogen atmosphere (1.5 atm) and then filtered through Celite*. The filtrate was concentrated under reduced pressure to give acetic acid 4-hydroxy-phenyl ester as a pale yellow oil (2.76 g, 91 % yield, 99 % pure by LC-MS and 1 H-NMR, no mass ion found). 10 1 H NMR (300 MHz, CDCl 3 ): 6 6.90 (d, 2H); 6.70 (d, 2H); 2.08 (s, 3H). Acetic acid 4-{3-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxyl propoxy}phenyl ester: To a stirred suspension of acetic acid 4-hydroxy-phenyl ester (211 mg, 1.39 mmol) in dry dichloromethane under nitrogen was added 6-[3-chloro-4-(3 15 hydroxy-propoxy)-phenyl]-4,5-dihydro-2H-pyridazin- 3 -one (302 mg, 1.07 mmol) and triphenylphosphine resin (polystyrene bound, 1.20 mmol/g loading, 1.80 g 2.16 mmol). The mixture was stirred at -10 'C for 10 minutes, then diisopropyl azodicarboxylate (DIAD, 310 !.L, 1.57 mmol) was added and the reaction mixture was allowed to warm to ambient temperature with stirring, then stirred at this temperature for 16 hours. The 20 mixture was filtered and the filtered residue rinsed alternately with dichloromethane (5 mL) and methanol (5 mL) (x3). The combined filtrates were evaporated to dryness and the residue was dry-loaded and purified by column chromatography on silica gel (20 g), eluting with a gradient of hexane / ethyl acetate (1:1) to neat ethyl acetate. Fractions with Rf= 0.46 (EtOAc) were combined and concentrated under reduced pressure to give acetic 25 acid 4-{ 3-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-phenoxy]-propoxy} phenyl ester as a colorless oil (393 mg, 88 % yield, 90 % pure by LC-MS and 'H-NMR). H NMR (300 MHz, CDCl 3 ): 5 7.51 (d, 1H); 7.42 (dd, 1H); 6.96 (dd, 2H); 6.69 (dd, 1H); 6.74 (dd, 2H); 3.94 (broad m, 4H total); 2.21 (in, 2H); 2.13 (in, 2H); 2.08 (s, 3H); 1.61 (in, 2H). 30 54 WO 2004/050657 PCT/US2003/037812 6-{3-Chloro-4- [3-(4-hydroxy-phenoxy)-propoxy -phenyl} -45-dihydro-2H-pyridazin-3 one: To a stirred solution of acetic acid 4-{3-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro pyridazin-3-yl)-phenoxy]-propoxy}-phenyl ester (393 mg, 0.94 mol) in tetrahydrofuran (5 mL), H 2 0 (4 mL) and methanol (1 mL) was added lithium hydroxide monohydrate (80.0 5 mg, 1.91 mmol). The reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 18 hours, quenched with glacial acetic acid (0.5 mL), and adsorbed onto silica gel (2 g). The mixture was evaporated to dryness under reduced pressure and dry loaded onto a silica gel column (10 g). Purification by column chromatography was carried out using hexane / ethyl acetate (20:80) as eluent. Fractions with Rf = 0.40 10 (EtOAc) were combined and evaporated to dryness. The residue was triturated with chloroform (1 mL) and dried under reduced pressure to give 6-{3-chloro-4-[3-(4 hydroxy-phenoxy)-propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3 -one as a colorless solid (230 mg, 65 % yield, 99 pure by LC-MS and 1 H-NMR). 'H NMR (300 MHz, CDCl 3 ): 5 7.50 (d, 1H); 7.41 (dd, 1H); 6.70 (dd, 1H); 6.62 (dd, 2H); 6.60 (dd, 2H); 3.94 (in, 4H 15 total); 2.22 (in, 2H); 2.13 (in, 2H); 1.62 (in, 2H). 6-{3-Chloro-4-[3-(4-oxiranylmethoxy-phenoxy)-propoxyl-phenyll-4,5-dihydro-2H pyridazin-3-one: To a stirred suspension of sodium hydride (60 % dispersion in mineral oil, 23.0 mg, 0.58 mmol) in NN-dimethylformamide (5 mL) under nitrogen at 0 *C was 20 added 6-{3-chloro-4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-4,5-dihydro-2H-pyrida zin-3-one (215 mg, 0.57 mmol) and the reaction mixture was stirred for 20 minutes at ambient temperature. A solution of 3-nitro-benzenesulfonic acid oxiranylmethyl ester (150 mg, 0.58 mmol) in N,N-dimethylformamide (2 mL) was added at 0 C. The mixture was stirred at ambient temperature for 16 hours, poured onto a mixture of ice and 25 saturated aqueous ammonium chloride solution (25 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (3 x 10 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure to give crude 6-{3-chloro 4-[3-(4-oxiranylmethoxy-phenoxy)-propoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one as a yellow gum, which was used without further purification in the next step. 30 55 WO 2004/050657 PCT/US2003/037812 6-(3 -Chloro-4-{3-[4-(2-hydroxy-3 -isopropylamino-propoxy)-phenoxyl -propoxyl phenyl)-4,5-dihydro-2H-pyridazin-3-one: To a stirred suspension of crude 6-{ 3-chloro-4 [3-(4-oxiranylmethoxy-phenoxy)-propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one in ethanol (5 mL) was added iso-propylamine (490 piL, 5.74 mmol). The reaction mixture 5 was heated to reflux and stirred at this temperature for 2 hours, allowed to cool to ambient temperature and evaporated to dryness under reduced pressure. The residue was dry loaded'and purified by column chromatography on silica gel (3 g) using a gradient of dichloromethane / methanol (9:1) to dichloromethane / methanol (4:1) as eluent. Fractions with Rf = 0.05 were combined and concentrated under reduced pressure. The 10 residue was recrystallised from ethanol to give 6-(3-chloro-4-{3-[4-(2-hydroxy-3 isopropylaminopropoxy)phenoxy]propoxy} -phenyl)-4,5-dihydro-2H-pyridazin-3-one (Example 8) as an off white solid (128 mg, 46 % yield over two steps, 98 % pure by LC MS and 'H-NMR). 'H NMR (300 MHz, CDC3): 8 7.51 (d, 1H); 7.40 (d, 1H); 6.71 (d, 1H); 6.66 (in, 4H); 4.09 (d, 2H); 3.96 (in, 1H); 3.94 (in, 4H); 2.97 (q, 1H); 2.70 (in, 2H); 15 2.21 (in, 2H); 2.13 (in, 2H); 1.61 (in, 2H); 1.05 (d, 6H total). The required pyridazinone glycol was prepared according to the method of Scheme VI-a. 56 WO 2004/050657 PCT/US2003/037812 Scheme VI-a OH AcO -CI O ' OAc O 7 o C O ' OAc CCI NaH, DMF AiCl 3 , CH 2
CI
2 0 OH 0 C1 O ' OAc O OH
H
2
NNH
2 LiOH CI EtOH Dioxane/water NH NH 0 0 5 Acetic acid 3-(2-chloro-phenoxy)-propyl ester: To a stirred suspension of sodium hydride (60 % dispersion in mineral oil, 7.40 g, 185 mmol) in NN-dimethylfornamide (150 mL) under nitrogen was added portionwise a solution of 2-chlorophenol (16.0 mL, 154 mmol) in NN-dimethylformamide (50 mL) at 0 'C. The reaction mixture was stirred 10 for 30 minutes at ambient temperature and a solution of acetic acid 3-chloro-propyl ester (21.0 mL, 170 mmol) in NN-dimethylformamide (50 mL) was added. The reaction mixture was stirred for 30 minutes at ambient temperature and then for 16 hours at 50 'C. After cooling to ambient temperature, the reaction mixture was poured into a mixture of ice and saturated aqueous ammonium chloride solution (250 mL), and extracted with 15 ethyl acetate (4 x 100 mL). The combined organic layers were washed with aqueous sodium hydroxide solution (1 N, 100 mL) and brine (2 x 100 mL), dried (MgSO 4 ) and evaporated to dryness to give acetic acid 3-(2-chloro-phenoxy)-propyl ester as a light orange oil (31.8 g, 90 % yield, 93 % pure by LC-MS and 'H-NMR). 'H NMR (400 MHz, CDCl 3 ): 6 7.16 (m, 1H); 7.03 (m, 111); 6.75-6.71 (m, 2H); 4.08 (m, 2H); 3.94 (m, 2H); 20 2.01 (s, 3H); 1.99 )m, 2H). 57 WO 2004/050657 PCT/US2003/037812 4-[4-(3-Acetoxy-propoxy)-3-chloro-phenyll-4-oxo-butyric acid: To a stirred solution of acetic acid 3-(2-chloro-phenoxy)-propyl ester (31.8 g, 139 mmol) in dichloromethane (100 mL) at ambient temperature under nitrogen was added succinic anhydride (20.8 g, 208 mmol). The reaction mixture was cooled in ice-water and aluminum trichloride (55.6 5 g, 417 mmol) was added portionwise whilst maintaining the temperature below 20 'C. The yellow suspension was stirred at ambient temperature for 20 minutes and then at 50 'C for 16 hours. The obtained dark purple highly viscous oil was allowed to cool to ambient temperature and then carefully hydrolysed with ice-water (100 ml) and ice aqueous hydrochloric acid (10 N, 100 ml). The aqueous layer was extracted with ethyl 10 acetate (5 x 100 mL). The combined organic layers were washed with saturated brine (2 x 100 mL), dried (Na 2
SO
4 ), and concentrated under reduced pressure to give an orange oil. The residue was re-dissolved in hot ethyl acetate (50 mL), hexane (200 mL) was added and the mixture was shaken for 10 minutes. After standing at ambient temperature for 1 hour, the supernatant was decanted. The residue was rinsed with 100 mL hexane 15 and dried under reduced pressure at 50 'C to give 4-[4-(3-acetoxy-propoxy)-3-chloro phenyl]-4-oxo-butyric acid as a yellow gum (42.7 g, 93 % yield, 90 % pure by LC-MS and 'H-NMR). 'H NMR (400 MHz, CDCl 3 ): 8 7.79 (in, 1H); 7.66 (in, 1H); 6.79 (in, 1H); 4.08 (in, 2H); 3.94 (in, 2H); 2.82 (in, 2H); 2.42 (in, 2H); 2.01 (s, 3H); 1.99 (in, 2H). 20 Acetic acid 3-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxyl-propyl ester: To a stirred suspension of 4-[4-(3-acetoxy-propoxy)-3-chloro-phenyl]-4-oxo butyric acid (42.7 g, 130 mmol) in ethanol (300 mL) at 0 *C was added a solution of hydrazine monohydrate (5.74 mL, 117 mmol) in ethanol (50 mL). The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 15 25 minutes before being heated to reflux and stirred at this temperature for 3 hours. Ethyl acetate (60 mL) was added to the hot solution and the mixture was allowed to cool to ambient temperature. The precipitate which formed was filtered off and washed with water (2 x 100 mL) and cold ethanol (2 x 100 mL), then dried with suction, and then under high vacuum to give acetic acid 3-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin 30 3-yl)-phenoxy]-propyl ester as light yellow powder (24.5 g, 58 % yield, 97 % pure by LC-MS and 'H-NMR). 'H NMR (400 MHz, CDCl 3 ): 6 7.52 (in, 1H); 7.40 (in, 1H); 6.72 58 WO 2004/050657 PCT/US2003/037812 (in, 1H); 4.08 (m, 2H); 3.94 (m, 2H); 2.22 (d, 1H); 2.01 (s, 3H); 1.99 (in, 2H); 1.63 (in, 2H). 6-{3-Chloro-4-(3-hydroxy-propoxy)-phenvll-4,5-dihydro-2H-pyridazin-3-one: To a 5 stirred suspension of acetic acid 3-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl) phenoxy]-propyl ester (24.5 g, 75.4 mmol) in 1,4-dioxane (125 mL) at ambient temperature were added water (125 mL) and lithium hydroxide (12.7 g, 302 mmol). The reaction mixture was stirred at ambient temperature for 3 hours and then acidified to pH 1-2 with aqueous hydrochloric acid (5 N, 100 mL) with stirring. After standing at 10 ambient temperature for 1 hour, the precipitate was filtered off and washed with water (2 x 100 mL) and cold ethanol (2 x 100 mL). The solid was dried under reduced pressure at 45 'C to give 6-[3-chloro-4-(3-hydroxy-propoxy)-pheny1]-4,5-dihydro-2H-pyridazin-3 one as off-white powder (19.2 g, 90 % yield, 99 % pure by LC-MS and 'H-NMR). 'H-NMR (400 MHz, CDCl 3 ): 8 7.52 (in, 1H); 7.40 (m, 1H); 6.72 (in, 1H); 3.94 (in, 2H); 15 3.53 (in, 2H); 2.21 (d, 2H); 1.90 (m, 2H); 1.60 (m, 2H) Example 9: N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3 bromophenoxy) propyl]-2-[2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3 yl))phenoxy]acetainide was prepared according to the method of Scheme VII. 20 59 WO 2004/050657 PCT/US2003/037812 Scheme VII OH OH Br 2 , CH 2
CI
2 Br 1. NaH, DMF N 3h at 0OC to r.t. 2. ' 0 N0 2 N NS0 /3 0 o O 1. iPrNH 2 (16 eq.), EtOH, O N Br reflux, 1.5 h B H 'NI~ ___ __Br" OH 0 2. 40% aq. MeNH 2 , r.t., N overnight 0 C1 N-NH H HO NNHBr O H 0 0, H N-NH EDC, HOAt, DMF, r.t. O N -O 0 0 5 2-[3-(3-Bromo-4-hvdroxy-phenoxv)-propyll-isoindole-1,3-dione: To a stirred solution of 2-[3-(4-hydroxy-phenoxy)-propyl]-isoindole-1,3-dione (1.20 g, 4.04 mmol) in dichloromethane (100 mL) was added dropwise a solution of bromine (210 pL, 4.04 mmol) in dichloromethane (30 mL) at 0-5 'C. The reaction mixture was stirred at 5 0 C for 3 hours. The precipitate which formed was filtered off, rinsed with cold 10 dichloromethane (10 mL) and dried under reduced pressure to give 2-[3-(3-bromo-4 hydroxy-phenoxy)-propyl]-isoindole-1,3-dione as a colorless solid (870 mg, 57 % yield, 98 % pure by LC-MS and 1 H-NMR). The filtrate was washed with aqueous sodium sulfite solution (5 wt%, 20 mL) and water (2 x 50 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give a second batch of 2-[3-(3-bromo-4-hydroxy-phenoxy) 15 propyl]-isoindole-1,3-dione as a light yellow powder (560 mg, 36 % yield, 90 % pure by LC-MS and 'H-NMR). 60 WO 2004/050657 PCT/US2003/037812 2-[3-(3-Bromo-4-(S)-oxiranylmethoxy-phenoxy)-ropyll-isoindole-1,3-dione: To a stirred suspension of sodium hydride (60 % dispersion in mineral oil, 35 mg, 0.877 mmol) in NN-dimethylformamide (4 mL) under nitrogen at 0 C was added a solution of 2-[3-(3-bromo-4-hydroxy-phenoxy)-propyl]-isoindole-1,3-dione (300 mg, 0.797 mmol) in 5 NN-dimethylformamide (2 mL) and the reaction mixture was stirred at ambient temperature for 20 minutes. A solution of (2S)-glycidyl m-nitrobenzenesulfonate (207 mg, 0.797 mmol) in NN-dimethylformamide (2 mL) was added at 0 C. The mixture was stirred at ambient temperature for 16 hours, poured onto a mixture of ice and saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (5 x 30 10 mL). The combined organic layers were washed with saturated brine (2 x 30 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure to give crude 2-[3-(3-bromo-4-(S) oxiranylmethoxy-phenoxy)-propyl]-isoindole-1,3-dione as a yellow gum, which was used without further purification in the next step. 15 1-[4-(3-Amino-propoxy)-2-bromo-nhenoxy -3-isopropylamino-(S)-propan-2-ol: To a stirred solution of crude 2-[3-(3-bromo-4-(S)-oxiranylmethoxy-phenoxy)-propyl]-iso indole- 1,3-dione from the previous step in ethanol (10 mL) was added iso-propylamine (700 RL, 8.22 mmol). The reaction mixture was heated to reflux and stirred at this temperature for 3 hours, allowed to cool to ambient temperature then concentrated under 20 reduced pressure. The residue was dissolved in methylamine (40 wt% in water, 10 mL), stirred at 30 'C for 16 hours, diluted with water (20 mL) and saturated brine (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with saturated brine (2 x 10 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure to give crude 1-[4-(3-amino-propoxy)-2-bromo-phenoxy]-3-isopropylamino-(S) 25 propan-2-ol as a colorless oil (230 mg, 80 % yield over three steps, 90 % pure by LC-MS and 'H-NMR), which solidified on standing. N-{3-[3-Bromo-4-((2S)-hydroxy-3-isopropylamino-propoxyl-phenoxyl-propyl}-2-r2 chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yt)-phenoxy]-acetamide: To a stirred 30 solution of [2-chloro-4-(6-oxo- 1,4,5,6-tetrahydro-pyridazin-3 -yl)-phenoxy] -acetic acid (162 mg, 0.573 mmol), 1-(3-dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride (EDC-HCl, 110 mg, 0.573 mmol) and 7-hydroxyazabenzotriazole (HOAt, 78 mg, 0.573 61 WO 2004/050657 PCT/US2003/037812 mmol) in NN-dimethylformamide (2.5 mL) under N 2 was added a solution of 1-[4-(3 amino-propoxy)-2-bromo-phenoxy]-3-isopropylamino-(S)-propan- 2 -ol (230 mg, 0.637 mmol) in NN-dimethylformamide (2.5 mL). The reaction mixture was stirred at ambient temperature for 3 hours, poured into saturated brine (20 mL), made strongly alkaline (pH 5 11-12) with aqueous sodium hydroxide solution (2 N), and extracted with ethyl acetate (5 x 20 mL). The combined organic layers were washed with saturated brine (2 x 10 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (3 g) eluting with dichloromethane / methanol (9:1). Fractions with Rf = 0.09 were combined and concentrated under reduced 10 pressure to give N-{3-[3-bromo-4-((2S)-hydroxy-3-isopropylamino-propoxy)-phenoxy] propyl}-2-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetamide as a colorless powder (130 mg, 33 % yield, 95 % pure by LC-MS and 1 H-NMR). Example 10: N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3 15 cyanophenoxy) propyl]-2-[2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3 yl))phenoxyjacetamide was prepared according to Scheme VIII. 62 WO 2004/050657 PCT/US2003/037812 Scheme VIII OH OH Br'o - CuCN/DMF NC 1. NaH, DMF NN 2. 0 0 O O0 2 N '0 O O 1. iPrNH 2 (10 eq.), EtOH, NCNC OH NCreflux1.5 h N5 H H 2. 40% aq. MeNH 2 , r.t., overnight CI HO N-NH NC OH H 00 H, H N-NH EDC, HOAt, DMF, r.t. 0 0 5-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propoxyl-2-hydroxy-benzonitrile: To a 5 stirred solution of 2-[3-(3-bromo-4-hydroxy-phenoxy)-propyl]-isoindole-1,3-dione (550 mg, 1.46 mmol) in NN-dimethylfonnamide (10 mL) was added copper (I) cyanide (160 mg, 1.75 mmol). The reaction mixture was then heated to 155 'C under nitrogen and stirred at this temperature for 9 hours. After allowing to cool to ambient temperature the solution was diluted with ethyl acetate (20 mL). A solution of ethylenediaminetetraacetic 10 acid (850 mg, 2.91 mmol) in water (20 mL) was added and the resulting suspension was stirred at ambient temperature for 1 hour. The two phases were separated and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL), dried (MgS04) and concentrated under reduced pressure. The residue was taken and filtered through a pad of silica gel (2 g) eluting with 15 ethyl acetate. The filtrate was evaporated to dryness under reduced pressure to give 5-[3 (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-2-hydroxy-benzonitrile as a brown powder (330 mg, 70 % yield, 85 % pure by LC-MS and 1 H-NMR). 63 WO 2004/050657 PCT/US2003/037812 5-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propoxyl-2-(S)-oxiranylmethoxy benzonitrile: To a stirred suspension of sodium hydride (60 % dispersion in mineral oil, 33 mg, 0.819 mmol) in NN-dimethylfonnamide (2 mL) under nitrogen at 0 "C was added a solution of 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-2-hydroxy-benzonitrile 5 (240 mg, 0.745 mmol) in NN-dimethylformamide (2 mL) and the reaction mixture was stirred at ambient temperature for 10 minutes. A solution of (2S)-glycidyl m nitrobenzenesulfonate (193 mg, 0.745 mmol) in NN-dimethylformamide (2 mL) was added at 0 'C. The reaction mixture was stirred at ambient temperature for 4 hours, poured onto a mixture of ice-water (10 mL) and saturated aqueous ammonium chloride 10 solution (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with a mixture of saturated brine (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) and then with saturated brine (2 x 20 mL). The organic layer was dried (Na 2
SO
4 ) and concentrated under reduced pressure to give crude 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-2-(S)-oxiranylmethoxy 15 benzonitrile (255 mg) as a light yellow solid, which was used in the next step without further purification. 5-(3-Amino-propoxy)-2-((2S)-hydroxy-3-isopropylamino-prooxy)-benzonitrile: To a stirred solution of crude 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-2-(S) 20 oxiranylnethoxy-benzonitrile in ethanol (10 mL) was added iso-propylamine (560 tL, 6.74 mmol). The reaction mixture was heated to reflux and stirred at this temperature for 3 hours then concentrated under reduced pressure. The residue was dissolved in methylamine (40 wt% in water, 10 mL) and the resulting solution was heated to 30 'C and stirred at this temperature for 16 hours. After cooling to ambient temperature the 25 solution was diluted with water (20 mL) and saturated brine (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with saturated brine (2 x 10 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure to give 5-(3-amino-propoxy)-2-((2S)-hydroxy-3-isopropylamino-propoxy)-benzonitrile as a yellow oil (140 mg, 67 % yield over three steps, 90 % pure by LC-MS and 1 H-NMR), 30 which solidified on standing. 64 WO 2004/050657 PCT/US2003/037812 2-[2-Chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl -phenoxyl-N-{ 3-[3-cyano-4 ((2S)-hydroxy-3-isopropylamino-propoxy)-phenoxcyl-propyll-acetamide hydrochloride: To a stirred solution of [2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy] acetic acid (116 mg, 0.410 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide 5 hydrochloride (EDC-HCI, 78 mg, 0.410 mmol) and 7-hydroxyazabenzotriazole (HOAt, 56 mg, 0.410 mmol) in NN-dimethylformamide (2.5 mL) under nitrogen was added a solution of 5-(3-amino-propoxy)-2-((2S)-hydroxy-3-isopropylamino-propoxy) benzonitrile (140 mg, 0.455 mmol) in NN-dimethylformamide (2.5 mL). The reaction mixture was stirred at ambient temperature for 3 hours, diluted with water (10 mL), 10 adjusted to pH 6 with aqueous hydrochloric acid (1 N), and washed with ethyl acetate (2 x 10 mL). The aqueous layer was left to stand at 5-10 'C for 16 hours. The precipitate which formed was filtered off, washed with water (2 x 10 mL) and dried under reduced pressure at 50 'C to give 2-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl) phenoxy]-N-{3-[3-cyano-4-((2S)-hydroxy-3-isopropylamino-propoxy)-phenoxy]-propyl} 15 acetamide hydrochloride as a colorless powder (80 mg, 34 % yield, 99 % pure by LC-MS and 1 H-NMR). Example 11: N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy} 2cyanophenoxy) propyl]-2- [2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3 20 yl))phenoxy]acetamide was prepared according to Scheme IX. 65 WO 2004/050657 PCT/US2003/037812 Scheme IX OMe 1. MeSCN, BCl 3 , OMe 1. NaH, DMF AICl3 2. 4N NaOH NC 2. OH OH Brn-~N 0 OMe OH BCIl/TBAI 1. NaH, DMF NC CH 2
CI
2 NC 0 2. OO N 0 2 N O 1. iPrNH 2 (10 eq.), EtOH, 0 : N reflux, 1.5 h OH H NC \ 2. 40% aq. MeNH 2 , r.t., O -N overnight NC N 0 CI OYNHH HO ON O H H 0 / 0 O NC ________________ H IN N-N H EDC, HOAt, DMF, r.t. O O 0 0 5 2-Hydroxy-5-methoxybenzonitrile: To a stirred solution of 4-methoxyphenol (12.4 g, 0.10 mol) in dry dichloromethane (400 ml) under nitrogen at 0 'C was added boron trichloride (1 M in dichloromethane, 100 mL, 0.10 mol) followed by methyl thiocyanate (8.2 mL, 0.12 mol). Anhydrous aluminium chloride (2.0 g, 15 mmol) was then added and the resulting suspension was stirred at ambient temperature for 16 hours. The reaction 10 mixture was then cooled to 0 *C and cold aqueous sodium hydroxide solution (4 N, 350 mL) was added. The resulting mixture was then heated to reflux and the dichloromethane was collected by distillation. After cooling to ambient temperature, cold aqueous hydrochloric acid (6 N, 300 mL) was added and the mixture was extracted with diethyl 66 WO 2004/050657 PCT/US2003/037812 ether (3 x 200 mL). The combined organic extracts were washed with saturated brine (2 x 300 mL) and dried (Na 2
SO
4 ) and concentrated under reduced pressure to give a pale yellow solid (15 g) with was purified by flash column chromatography over silica gel to give 2-hydroxy-5-methoxybenzonitrile as a pale yellow solid (10.4 g, 70 % yield, 100 % 5 pure by LC-MS and 'H-NMR). 2-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propoxyl-5-methoxy-benzonitrile: To a stirred suspension of sodium hydride (60 % dispersion in mineral oil, 450 mg, 11.3 mmol) in NN-dimethylformamide (10 mL) under nitrogen at 0 'C was added portionwise 10 a solution of 2-hydroxy-5-methoxy-benzonitrile (1.40 g, 9.39 mmol) in N,N dimethylformamide (10 mL) and the reaction mixture was stirred at ambient temperature for 10 minutes. A solution of 2-(3-bromopropyl)-isoindole-1,3-dione (2.82 g, 10.5 mmol) in NN-dimethylformamide (20 mL) was added at 0 'C and the reaction mixture was stirred at ambient temperature for 16 hours, poured into ice-water (200 mL) and left to 15 stand at ambient temperature for 15 minutes. The formed precipitate was filtered off with suction, washed with water (25 mL) and diethyl ether (25 mL) then dried under reduced pressure to give 2-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-5-methoxy benzonitrile as a light yellow solid (2.51 g, 79 % yield, 99 % pure by LCMS and 1
H
NMR). 20 2-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propoxyl-5-hydroxy-benzonitrile: To a stirred solution of 2-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-5-methoxy benzonitrile (1.09 g, 3.24 mmol) and tetra-n-butylammonium iodide (1.28 g, 3.47 mmol) in dry dichloromethane (20 ml) at -78 'C was added boron trichloride (1 M in 25 dichloromethane, 14.6 mL, 14.6 mmol) maintaining the internal temperature below 60 'C. The reaction mixture was stirred at -78 'C for 10 minutes, allowed to warm to ambient temperature then stirred for a further 2 hours at ambient temperature. The mixture was then poured onto cold saturated aqueous sodium hydrogen carbonate solution (80 mL). The organic layer was separated and the aqueous layer was extracted 30 with dichloromethane (2 x 50 mL). The combined organic layers were washed with water (100 mL), saturated brine (2 x 100 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography 67 WO 2004/050657 PCT/US2003/037812 over silica gel eluting with dichloromethane / methanol (99.5:0.5) to give 2-[3-(1,3-dioxo 1,3-dihydro-isoindol-2-yl)-propoxy]-5-hydroxy-benzonitrile as a colorless solid (773 mg, 74 % yield, 99 % pure by LC-MS and 'H-NMR). 5 2-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propoxyl-5-(S)-oxiranylmethoxy benzonitrile: To a stirred suspension of sodium hydride (60 % dispersion in mineral oil, 49 mg, 1.23 mmol) in NN-dimethylformamide (2 mL) under nitrogen at 0 "C was added a solution of 2-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-5-hydroxy-benzonitrile (369 mg, 1.14 mmol) in NN-dimethylformamide (2 mL) and the reaction mixture was 10 stirred at ambient temperature for 10 minutes. A solution of (2S)-glycidyl m nitrobenzenesulfonate (7, 323 mg, 1.25 mmol) in NN-dimethylformamide (2 mL) was then added at 0 'C. The reaction mixture was stirred at ambient temperature for 16 hours then poured onto a mixture of ice-water (15 mL) and saturated aqueous ammonium chloride solution (15 mL), and the resulting mixture was extracted with ethyl acetate (4 x 15 20 mL). The combined organic extracts were washed with water (2 x 50 mL) and saturated brine (50 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel using a gradient eluent neat dichloromethane to dichloromethane / ethyl acetate (9:1) to give 2-[3-(1,3 dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-5-(S)-oxiranylmethoxy-benzonitrile as a 20 colorless solid (362 mg, 84 % yield, 99 % pure by LC-MS and 'H-NMR). 2-(3-Amino-propoxy)-5-((2S)-hydroxy-3-isopropylamino-propoxy)-benzonitrile: To a stirred solution of 2-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-5-(S) oxiranylmethoxy-benzonitrile (240 mg, 0.634 mmol) in ethanol (7 mL) was added iso 25 propylamine (540 ptL, 6.34 mmol). The reaction mixture was heated to reflux and stirred at this temperature for 2 hours. After allowing to cool to ambient temperature, the solution was then concentrated under reduced pressure. The residue was dissolved in methylamine (40 wt% in water, 7 mL), heated to 30 'C and stirred at this temperature for 16 hours. After cooling to ambient temperature, the solution was diluted with water (10 30 mL) and saturated brine (10 mL) then extracted with dichloromethane (4 x 10 mL). The combined organic extracts were washed with water (2 x 10 mL) and saturated brine (2 x 20 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure to give crude 2-(3 68 WO 2004/050657 PCT/US2003/037812 amino-propoxy)-5-((2S)-hydroxy-3-isopropylamino-propoxy)-benzonitrile as a colorless oil (176 mg, 90 % yield, 90 % pure by LC-MS and 1 H-NMR), which solidified on standing. 5 2-[2-Chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxyl-N-{3-[2-cyano-4 ((2S)-hydroxy-3-isopropylamino-propoxy)-phenoxyl-propyll-acetamide hydrochloride: To a stirred solution of [2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy] acetic acid (146 mg, 0.515 mmol), 1-(3-dimethylaninopropyl)-3-ethyl carbodiimide hydrochloride (EDC-HCl, 99 mg, 0.515 mmol) and 7-hydroxyazabenzotriazole (HOAt, 10 70 mg, 0.515 mmol) in NN-dimethylformamide (3 mL) under nitrogen was added a solution of 2-(3-amino-propoxy)-5-((2S)-hydroxy-3-isopropylamino-propoxy) benzonitrile (176 mg, 0.573 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at ambient temperature for 4 hours, diluted with water (20 mL) and washed with ethyl acetate (40 mL). The aqueous layer was left to stand at 5-10 *C for 15 16 hours. The precipitate which formed was filtered off and the solid was washed with water (2 x 10 mL) and dried under reduced pressure at 60 'C to give 2-[2-chloro-4-(6 oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-N-{ 3-[2-cyano-4-((2S)-hydroxy-3 isopropylamino-propoxy)-phenoxy]-propyl}-acetamide hydrochloride as a colorless powder (196 mg, 66 % yield, 99 % pure by LC-MS and 'H-NMR). 20 The compounds of Examples 12-15 can be prepared using variations of the previously described syntheses. Example 12: (6-{4-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3 25 bromophenoxy)propoxy] -3-chlorophenyl} -2,4,5-trihydropyridazin-3 -one) is prepared as shown in Scheme X. Following cleavage of the silyl-protected phenolic group, the hydroxyl is reacted successively with (2S)-glycidyl m-nitrobenzenesulfonate and isopropylamine to deliver the compound of Example 12. 69 WO 2004/050657 PCT/US2003/037812 Scheme X O Br OH TBDMS (3 eq.), imidazole OTBDMS _2 Br (3 eq.) Br
CH
2
CI
2 | THF, reflux, 2 hr OBn OBn OBn OH OTBDMS Br OTBDMS N-NH
H
2 /Pd-C Br O Cl EtOH OH Polymer supported PPh 3 (2 eq) DIAD (1.4 eq.), CH 2 Cl2 / OH CI Br TBAF
CH
2
CI
2 CIN 5 Example 13: (2-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-5-{3-[2-chloro-4-(6 oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]propoxy}benzenecarbonitrile) is prepared by reacting 3-bromo-4-(1,1,2,2-tetramethyl-1-silapropoxy)phenol, from Scheme X above, with copper cyanide in DMF to produce 5-hydroxy-2-(1,1,2,2-tetramethyl- 1 -silapropoxy) 10 benzenecarbonitrile (Scheme XI). This compound is converted to Example 13 by the same sequence of steps as used for Example 12 in Scheme X. Scheme XI OTBDMS OTBDMS Br CuCN,DMF CN OH OH 70 WO 2004/050657 PCT/US2003/037812 Example 14: (6-{4-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2 bromophenoxy)propoxy] -3 -chlorophenyl} -2,4,5-trihydropyridazin-3-one) is synthesized starting from 3-bromo-4-hydroxyphenyl acetate, as shown in Scheme XII. 5 Following coupling of this compound with the pyridazinone glycol as described in Scheme VI for Example 8, the oxygen protecting group is removed by mild hydrolysis and the phenol is converted to Example 8 by the standard sequence of reactions already described. 10 Example 15: (5-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2-{3-[2-chloro-4-(6 oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]propoxy}benzenecarbonitrile) is likewise prepared by the method of Scheme XII, starting with 3-cyano-4-hydroxyphenyl acetate. Scheme XII 15 OH N-NH OAc OAc o O / O Ci Br ci LiOH/H 2 0 BrOH Polymer supported PPha ( 2 eq) THF/MeOH OHO NH 0 OH _______O Y N H Br CI OH H OO Br Cl - N-NH 1O 71 WO 2004/050657 PCT/US2003/037812 PDE-3 inhibitory activity Example 16: Assay for measuring cAMP PDE-3 inhibitory activity Human platelet cyclic AMP phosphodiesterase is prepared according to the 5 method of Alvarez et al., Mol. Pharmacol. 29: 554 (1986). The PDE incubation medium contains 10 mM Tris-HCI buffer, pH 7.7, 10 mM MgSO 4 , and 1 pM [ 3 H]AMP (0.2 gCi) in a total volume of 1.0 mL. Test compounds are dissolved in DMSO immediately prior to addition to the incubation medium, and the resulting mixture is allowed to stand for 10 minutes prior to the addition of enzyme. Following the addition of PDE, the contents are 10 mixed and incubated for 10 minutes at 30 'C. Three assays each are performed for each of five test compound concentrations, the mean of the determinations (n = 3) at each concentration is plotted, and IC 5 o values are determined graphically. The results are tabulated in Table I. 15 P-Adrenergic Receptor Binding Activity B-Adrenergic receptor binding and blocking activity is evaluated by one or more of the methods below. The results are tabulated in Table I. Example 17: Radioligand for measuring p,-receptor affinity 20 pr-Adrenergic receptor binding is measured in human recombinant beta-1 receptors expressed in CHO-REX16 cells, using [1251] (-) lodocyanopindolol (2000 Ci/mmol) as the radioligand, as described in Kalaria et al., J. Neurochem. 53: 1772-81 (1998), and Minneman et al., Mol. Pharmacol. 16: 34-46 (1979). 25 Example 18: Radioligand for measuring p2-receptor affinity p 2 -Adrenergic receptor binding is measured in human recombinant beta-2 receptors expressed in CHO-WT21 cells, using [ 1 25 I] (-) lodocyanopindolol (2000 Ci/mmol) as the radioligand, as described in Kalaria et al. (1998) and Minneman et al. (1979), supra. 30 72 WO 2004/050657 PCT/US2003/037812 Example 19: Determination of b 2 -adrenergic blocking activity in the guinea pig Tracheal chains are prepared as described by Castillo and DeBeer, J. Pharm. Exp. Ther. 90: 104 (1947), suspended in tissue baths maintained at 37 *C containing Tyrodes solution gassed with 95% 02-5% CO 2 , and attached to an isometric force-displacement 5 transducer. After an equilibration period of 2 hours, the preparations are induced to contract with carbachol (3 x 10- M), and relaxation is induced with cumulative dose response curves for isoproterenol first in the absence of and then in the presence of the test compound. A contact time of 10 minutes is allowed for all test compounds. Affinity constants are determined by comparing the shift in the dose-response curve for each test 10 compound with that of isoproterenol (EC 5 o = 2.3 x 0.2 x 108 M). Example 20: Assay for measuring contraction-relaxation in guinea pig papillary muscle Male guinea pigs (400-500 g) are killed by cervical dislocation and the hearts are quickly removed, immersed in ice-cold, and oxygenated in Kreb's solution containing 15 113.1 mM NaCl, 4.6 mM KCl, 2.45 mM CaCl 2 , 1.2 mM MgCl 2 , 22.0 mM NaH 2
PO
4 , and 10.0 mM glucose; pH 7.4 with 95% 02 - 5% CO 2 . The ventricles are opened and papillary muscles are removed with chordae tandineae and a base of surrounding tissue intact. The tendinous ends of the muscles are ligated with silk thread, and the muscles are mounted in vertical, double-jacketed organ baths containing 10 mL of oxygenated Kreb's 20 solution kept at 37 'C. The tendinous end is attached to a Grass isometric force transducer, while a metal hook is inserted into the base of the muscle. Following a 45-minute equilibration period under a 1 gram tension, control contractions are elicited by stimulating the muscle using stainless steel field electrodes at a frequency of 1.0 Hz, 2.0 ms duration. The amplitude of the stimulus is adjusted to be 25 approximately 1.5 times the threshold amplitude sufficient to elicit a contraction of the tissues. Control contraction-relaxation cycles are recorded for 30 seconds continuously. Cumulative test drug concentrations are then injected directly into the bath while the tissue is being stimulated. Contraction-relaxation recordings are made continuously, for 30 seconds per test compound concentration. A series of washout contractions is 30 recorded following a change of solution. Provided that the amplitude of contraction returns to that measured in control conditions, a single concentration of positive control is then tested on the tissue in the same manner as the test compound. 73 WO 2004/050657 PCT/US2003/037812 Contraction amplitude as well as the time courses of contraction and relaxation are quantified. All recordings are normalized against control values; statistical analysis of the results is made using t-tests or ANOVAs. All publications, patents and patent applications identified above are herein 5 incorporated by reference. The invention being thus described, it will be apparent to those skilled in the art that the same may be varied in many ways without departing from the spirit and scope of the invention. Such variations are included within the scope of the invention to be claimed. 74

Claims (49)

1. A compound of formula (I) p-(Ar),-(L)m -X (I) 5 or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: m is chosen from 0 and 1; n is chosen from 0 and 1; 10 P is chosen from a 2-amino-i -hydroxyeth- l-yl radical, N-substituted-2-amino- 1 hydroxyeth-1-yl radicals, N-N-disubstituted-2-amino-l-hydroxyeth-1-yl radicals, a 3 amino-2-hydroxypropoxy radical, N-substituted-3-amino-2-hydroxypropoxy radicals, and N-N-disubstituted-3-amino-2-hydroxypropoxy radicals; Ar is chosen from aryl radicals and heteroaryl radicals, which aryl and heteroaryl 15 radicals are optionally substituted with one to three substituent(s) chosen from R 2 , R 3 , and R4; R 2 , R 3 , and R 4 are independently chosen from C-C 8 alkyl radicals, C 2 -Cs alkenyl radicals, C 2 -C 8 alkynyl radicals, C-C 4 alkylthio groups, C-C 4 alkoxy groups, halo radicals, a nitro group, a cyano group, a trifluoromethyl group, -NR 5 R 6 groups, 20 acylaminoalkyl radicals, -NHSO 2 R 1 groups and -NHCONHRi groups, wherein one or more -CH 2 - group(s) of the alkyl, alkenyl and alkynyl radicals is/are optionally replaced with -0-, -S-, -SO 2 - and/or -NRs-, and the alkyl, alkenyl and alkynyl radicals are optionally substituted with one or more substituent(s) chosen from an oxo group and a hydroxyl group; 25 R 5 and R 6 are independently chosen from a lone pair of electrons, a hydrogen radical, C-C 8 alkyl radicals, C 2 -C 8 alkenyl radicals and C 2 -CS alkynyl radicals, wherein the alkyl, alkenyl and alkynyl radicals are optionally substituted with a substituent chosen from a phenyl radical and substituted phenyl radicals; 75 WO 2004/050657 PCT/US2003/037812 R 1 is chosen from Ci-C 8 alkyl radicals, C 3 -C 8 cycloalkyl radicals, C 2 -C 8 alkenyl radicals, C 3 -C 8 cycloalkenyl radicals, C 2 -C 8 alkynyl radicals and C 3 -C 8 cycloalkynyl radicals; L is chosen from a direct bond, CI-C 1 2 alkylene radicals, C 2 -C 12 alkenylene 5 radicals and C 2 -C 12 alkynylene radicals, wherein one or more -CH 2 - group(s) of the alkylene, alkenylene and alkynylene radicals is/are optionally replaced with -0-, -S-, -SO 2 - and/or -NR 5 -, and the alkylene, alkenylene and alkynylene radicals are optionally substituted with one or more substituent(s) independently chosen from an oxo group and a hydroxyl group; and 10 X is chosen from moieties of formulas A-Q: R RI R N O R N AR R R R R 0R A RB R / N R N'N 0 H R C D R .. 0 0 RN' R N S, N R 15E F 60 R GR 15 F G 76 WO 2004/050657 PCT/US2003/037812 R R R R R -N R N O >/ -R R N R NN.N R N-NH H R H O H N R HN R ON OH P R R R N 0R R R R i R r R R r N H R Q,/ HN--y R N H N 0- Sb N 0 P o N N-NH // 0 N R R R Q wherein one R group of moieties A-Q forms a covalent bond between X and L when m is 1, or between X and Ar when nis 1 and m isO0, or 10 between X and J3 when n is 0 and m is 0; and each remaining R group of moieties A-Q is independently chosen from a hydrogen radical, halo radicals, a nitro group, a cyano group, a trifluoromethyl group, an amino group, NR 5 R 6 groups, C 1 -C 4 alkoxy radicals, C 1 -C 4 alkylthio radicals, COOR 1 radicals, Ci-C 1 2 alkyl radicals, C 2 -C 12 alkenyl radicals and C 2 -C 12 15 alkynyl radicals, wherein one or more -CH 2 - group(s) of the alkyl, alkenyl and alkynyl radicals is/are optionally replaced with -0-, -S-, -SO 2 - and/or 77 WO 2004/050657 PCT/US2003/037812 NR 5 -, and the alkyl, alkenyl and alkynyl radicals are optionally substituted with one or more substituent(s) chosen from an oxo group and a hydroxyl group; and with the following provisos: 5 (a) when m+n is 0, when X is chosen from A moieties, when P is chosen from a 2-amino-1 -hydroxyeth- 1 -yl radical, N-substituted-2-amino 1 -hydroxyeth- 1-yl radicals, and N-N-disubstituted-2-amino- 1 -hydroxyeth 1-yl radicals, and (i) when P is at position 3 or 4 of A, 5 4 6 * ' N 3 7 N 0 8 H 10 1 then the N-substituted-2-amino- 1 -hydroxyeth- l-yl radicals are not substituted with an alkyl radical, a cycloalkyl radical; an alkenyl radical; a cycloalkenyl radical, or an alkynyl radical; and then one substituent of the N-N-disubstituted-2-amino- 1 15 hydroxyeth- 1-yl radicals is not an alkyl radical, a cycloalkyl radical; an alkenyl radical; a cycloalkenyl radical, or an alkynyl radical; (ii) when P is at position 5 of A, then position 8 of A is not substituted with an alkoxy radical or a hydroxyl radical; (iii) when P is at position 6 of A, position 8 of A is not 20 substituted with an alkoxy radical, an acyloxy radical, or a hydroxyl radical; and (iv) when p is at position 8 of A and position 5 of A is substituted with an alkoxy radical or a hydroxy radical, then the N substituted-2-ainino-1-hydroxyeth-1-yl radicals are not substituted 25 with an alkyl radical or a cycloalkyl radical; and then one substituent of the N-N-disubstituted-2-amino- 1 hydroxyeth-1 -yl radicals is not an alkyl radical or a cycloalkyl radical 78 WO 2004/050657 PCT/US2003/037812 (b) when m+n is 0, when X is chosen from A moieties, when P is chosen from a 3-amino-2-hydroxypropoxy radical, N-substituted-3-amino
2-hydroxypropoxy radicals, and N-N-disubstituted-3-amino-2 hydroxypropoxy radicals, and 5 (i) when P is at position 4 of A, then any R attached to the ring nitrogen is not a Ci-C 3 alkyl radical or a C-C 3 alkenyl radical; (ii) when P is at any position 5-8 of A, then the N substituted-3-amino-2-hydroxypropoxy radicals are not substituted with an alkyl radical; a cycloalkyl radical; an alkenyl radical; a 10 cycloalkenyl radical; or an alkynyl radical; and then one substituent of the N-N-disubstituted-3-amino-2 hydroxypropoxy radicals is not an alkyl radical; a cycloalkyl radical; an alkenyl radical; a cycloalkenyl radical; or an alkynyl radical; (c) when m is 1, when n is 0, when X is chosen from A moieties, when 15 0 is chosen from a 3-amino-2-hydroxypropoxy radical, N-substituted-3 amino-2-hydroxypropoxy radicals, and N-N-disubstituted-3-amino-2 hydroxypropoxy radicals, and when P is at position 5 of A, and position 8 of A is substituted with a hydrogen radical, an alkoxy radical, or an aryloxy radical, and the R attached to the ring nitrogen is a hydrogen 20 radical or an alkyl radical, then L is not a C 3 alkenyl radical; and (d) when m+n is 0, when X is chosen from J moieties, when P is chosen from a 3-amino-2-hydroxypropoxy radical, N-substituted-3 -amino 2-hydroxypropoxy radicals, and N-N-disubstituted-3-amino-2 hydroxypropoxy radicals, and when P is attached to the phenyl ring of J, 25 then the N-substituted-3-amino-2-hydroxypropoxy radicals and the N-N disubstituted-3-amino-2-hydroxypropoxy radicals are not substituted with a C 3 -C 4 alkyl radical or a phenethyl radical. 2. The compound of claim 1, wherein L is chosen from C-C 12 alkylene 30 radicals, C 2 -C 1 2 alkenylene radicals, and C 2 -CI 2 alkynylene radicals. 79 WO 2004/050657 PCT/US2003/037812
3. The compound of claim 2, wherein one or more -CH 2 - group(s) of the alkylene, alkenylene and alkynylene radicals is/are optionally replaced with -0- and/or -NR 5 -, and the alkylene, alkenylene and alkynylene radicals are optionally substituted with one or more oxo group(s). 5
4. The compound of claim 3, wherein L is chosen from -O(CH 2 ) 3 0-, -O(CH 2 ) 3 NH(CO)CH 2 0-, and -O(CH 2 ) 3 NH(CO)(CH 2 ) 3 0-.
5. The compound of claim 1, wherein X is chosen from moieties of formulas 10 B, E, and O.
6. The compound of claim 1, wherein: n is 1; and X is chosen from moieties of formula A. 15
7. The compound of claim 1, wherein: m+n is 1 or 2; and X is chosen from moieties of formula J. 20
8. The compound of claim 1, wherein the R groups of moieties A-Q are independently chosen from a hydrogen radical; C 1 -C 12 alkyl radicals; C 2 -C 12 alkenyl radicals; and C 2 -C 12 alkynyl radicals.
9. The compound of claim 1, wherein the R groups of moieties A-Q are 25 independently chosen from a hydrogen radical; C 1 -C 6 alkyl radicals; C 2 -C 6 alkenyl radicals; and C 2 -C 6 alkynyl radicals.
10. The compound of claim 1, wherein Ri is chosen from Ci-C 6 alkyl radicals, C 1 -C 6 cycloalkyl radicals, C 2 -C 6 alkenyl radicals, C 2 -C 6 cycloalkenyl radicals, and C 2 -C 6 30 alkynyl radicals. 80 WO 2004/050657 PCT/US2003/037812
11. The compound of claim 1, wherein R 2 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals, C-C 4 alkoxy groups; C-C 4 alkylthio groups; C-C 8 alkyl radicals; C 2 -Cs alkenyl radicals; and C 2 -C 8 alkynyl radicals. 5
12. The compound of claim 1, wherein R 3 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals; C-C 4 alkoxy groups; CI-C 4 alkylthio groups; C-C 8 alkyl radicals; C 2 -Cs alkenyl radicals; and C 2 -C 8 alkynyl radicals. 10
13. The compound of claim 1, wherein R4 is chosen from a cyano group; a nitro group; halo radicals; a hydrogen radical; a trifluoromethyl group; acylaminoalkyl radicals; CI-C 4 alkoxy groups; C-C 4 alkylthio groups; CI-C 8 alkyl radicals; C 2 -C 8 alkenyl radicals; and C 2 -C 8 alkynyl radicals. 15
14. The compound of claim 1, wherein R 5 is chosen from a lone pair of electrons; a hydrogen atom; C-C 8 alkyl radicals; C 2 -C 8 alkenyl radicals; and C 2 -C 8 alkynyl radicals. 20
15. The compound of claim 1, wherein R 6 is chosen from a lone pair of electrons; a hydrogen atom; C-C 8 alkyl radicals; C 2 -C 8 alkenyl radicals; and C 2 -C 8 alkynyl radicals.
16. The compound of claim 1, wherein Ar is chosen from a phenyl radical, a 25 naphthyl radical, a pyridyl radical, an isoxazoyl radical, a pyridyl radical, a quinolyl radical, and an isoquinolyl radical.
17. The compound of claim 16, wherein Ar is a phenyl radical. 30
18. The compound of claim 1, wherein Ar is chosen from groups Arj-Ar 7 : 81 WO 2004/050657 PCT/US2003/037812 (P) \' V\ (3)(3 V (CH 2 )n ) N\ j(1)-- V = 0, C=O, S, N, CH 2 ( ~)NN n = 1-3 P ((1) Np W = 0, S,N U -CH 2 CH 2 -, U = -CH 2 CH 2 -, -CH=CH=, -CH=CH=, 0, S, N, or a bond 0, S, N, or a bond wherein (ax) indicates the position where Ar may bond to P, L, and X. 5
19. The compound of claim 1, wherein P is chosen from a 2-amino-1 hydroxyeth- 1-yl radical, N-substituted-2-amino- 1 -hydroxyeth- 1-yl radicals, and N-N disubstituted-2-amino- 1 -hydroxyeth- 1-yl radicals, wherein the carbon at position 1 of each radical is enriched over its mirror image counterpart. 10
20. The compound of claim 1, wherein P is chosen from a 3-amino-2 hydroxypropoxy radical, N-substituted-3-amino-2-hydroxypropoxy radicals, and N-N disubstituted-3-amino-2-hydroxypropoxy radicals, wherein the carbon at position 2 of each radical is enriched over its mirror image counterpart. 15
21. The compound of claim 1, wherein m+n is 0.
22. The compound of claim 1, wherein m+n is 1.
23. The compound of claim 1, wherein m+n is 2. 20
24. The compound of claim 1, which is chosen from: 82 WO 2004/050657 PCT/US2003/037812 6-{2-hydroxy-3-[(methylethyl)amino]-propoxy} -4,3a-dihydroimidazolidino [2,1 b]-quinazolin-2-one; 5-[(4-{2-hydroxy-3-[(methylethyl)-amino propoxy}phenyl)carbonyl-4-methyl-4 imidazolin-2-one; 5 6-[3-(2-{2-hydroxy-3-[(methylethyl)-amino] propoxy}phenoxy)propoxy]-4,3a dihydro- imidazolidino[2,1-b]quinazolin-2-one; 5-({4-[3-(2-{2-hydroxy-3-[(methyethyl-aminopropoxy}phenoxy)propoxy] phenyl}carbonyl)-4-methyl-4-imidazolin-2-one; N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)-amino]propoxy}phenoxy)propyl]-2-[2 10 chloro-4-(6-oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]acetamide; 6-{4-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl) anino]propoxy}-phenoxy) propoxy] -3-chlorophenyl} -2,4,5-trihydropyridazin-3-one; N-[3-(4-{ (2S)-2-hydroxy-3-[(methylethyl)-amino]propoxy}-phenoxy)propyl]-2 [4-(5- cyano-2-methyl-6-oxo(3-hydropyridyl) phenoxy]acetamide; 15 N-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl) amino] propoxy}phenoxy)propyl]-4 (2-oxo(6-hydroquinolyl-oxy))butanamide; N-[3-(4-{ (2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3 bromophenoxy)propyl]-2-[2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3 yl))phenoxy]acetamide; 20 N-[3-(4-{ (2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3 cyanophenoxy)propyl]-2-[2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3 yl))phenoxy]acetamide; N-[3-(4-{ (2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2 cyanophenoxy)propyl]-2-[2-chloro-4-(6-oxo(1,4,5-trihydropyridazin-3 25 yl))phenoxy]acetamide; 6-{4-[3-(4-{ (2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-3 bromophenoxy)propoxy] -3-chlorophenyl} -2,4,5-trihydropyridazin-3-one; 2-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-5-{3-[2-chloro-4-(6 oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]propoxy}benzenecarbonitrile; 30 6-{4-[3-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2 bromophenoxy)propoxy] -3-chlorophenyl } -2,4,5-trihydropyridazin-3-one; and 83 WO 2004/050657 PCT/US2003/037812 5-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2-{3-[2-chloro-4-(6 oxo(1,4,5-trihydropyridazin-3-yl))phenoxy]propoxy}benzenecarbonitrile.
25. A pharmaceutical composition comprising: 5 (i) an effective amount of any compound of claims 1-24; and (ii) a pharmaceutically-acceptable carrier.
26. The pharmaceutical composition of claim 25, wherein the pharmaceutically-acceptable carrier is chosen from wetting agents, buffering agents, 10 suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, sweeteners and therapeutic agents other than those compounds of claim 1.
27. The pharmaceutical composition of claim 25, wherein the 15 pharmaceutically-acceptable carrier is chosen from fillers, diluents, excipients, and solvent encapsulating materials.
28. The pharmaceutical composition of claim 25, wherein the pharmaceutically-acceptable carrier is active. 20
29. The pharmaceutical composition of claim 25, wherein the pharmaceutically-acceptable carrier is chosen from: (1) sugars; (2) starches; (3) cellulose band its derivatives; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients; (9) oils; (10) glycols; (11) polyols; (12) esters; (13) agar; (14) buffering 25 agents; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; and (21) polyesters, polycarbonates and polyanhydrides.
30. The pharmaceutical composition of claim 25, wherein the 30 pharmaceutically-acceptable carrier is chosen from lactose, glucose, sucrose, corn starch, potato starch, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, cocoa butter, suppository waxes, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, 84 WO 2004/050657 PCT/US2003/037812 corn oil, soybean oil, propylene glycol, glycerin, sorbitol, mannitol, polyethylene glycol, ethyl oleate, ethyl laurate, magnesium hydroxide solutions, and aluminum hydroxide solutions. 5
31. The pharmaceutical composition of claim 25, wherein the pharmaceutically-acceptable carrier is liquid.
32. The pharmaceutical composition of claim 25, wherein the pharmaceutically-acceptable carrier is solid. 10
33. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition has a form chosen from solids and liquids.
34. The pharmaceutical composition of claim 25, wherein the pharmaceutical 15 composition has a form chosen from drenches, tablets, boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, mouth sprays, emulsions, microemulsions, sterile solutions, sterile suspensions, sustained-release formulations, creams, ointments, controlled-release patches, controlled-release topical sprays; pessaries, and foams. 20
35. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition has a form chosen from aqueous solutions, non-aqueous solutions, aqueous suspensions, non-aqueous suspensions, tablets for buccal adsorption, tablets for sublingual adsorption, and tablets for systemic absorption. 25
36. A method of regulating calcium homeostasis in a mammal in need thereof, comprising administering to the mammal an effective amount of any one compound of claims 1-24. 30
37. A method of treating cardiovascular disease, stroke, and/or epilepsy in a mammal in need thereof, comprising administering to the mammal an effective amount of any one compound of claims 1-24. 85 WO 2004/050657 PCT/US2003/037812
38. A method of claim 37, wherein the cardiovascular disease is chosen from heart failure, hypertension, SA/AV node disturbance, arrythmia, hypertrophic subaortic stenosis, and angina. 5
39. The method of claim 38, wherein the heart failure is chronic heart failure or congestive heart failure.
40. A method of inhibiting p-adrenergic receptors and/or inhibiting phosphodiesterase PDE of a mammal in need thereof, comprising administering to the 10 mammal an effective amount of any one compound of claims 1-24.
41. The method of claim 40, wherein both p-adrenergic receptors and PDE are inhibited. 15
42. The method of claim 40, wherein PDE3 is inhibited.
43. The method of claim 40, wherein administering is by oral administration, by parenteral administration, by inhalation spray, by topical administration, by rectal administration, by nasal administration, by buccal administration, by vaginal 20 administration, or administration an implanted reservoir.
44. The method of claim 40, wherein administering is by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, or intraosseous injection. 25
45. The method of claim 40, wherein administering is by an infusion technique.
46. The method of claim 40, further comprising administering one or more 30 additional therapeutic agents for simultaneous, separate, or sequential use. 86 WO 2004/050657 PCT/US2003/037812
47. The method of claim 46, wherein the one or more additional agent are chosen from therapeutic agents.
48. A method of claim 47, wherein the therapeutic agents are administered (i) 5 together in a single formulation with the compound of claim 1 or (ii) separately in individual formulations designed for optimal release rates of their respective active agent.
49. The method of any one of claims 36-48, wherein the mammal is a human. 87
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Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1575923A2 (en) * 2002-12-23 2005-09-21 Artesian Therapeutics, Inc. CARDIOTONIC COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST &bgr;-ADRENERGIC RECEPTORS AND PHOSPHODIESTERASE
DE102004011512B4 (en) 2004-03-08 2022-01-13 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical preparation containing pimobendan
US8980894B2 (en) 2004-03-25 2015-03-17 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure
EP1579862A1 (en) 2004-03-25 2005-09-28 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure
US20090111730A1 (en) 2004-07-08 2009-04-30 Novo Nordisk A/S Polypeptide protracting tags
JP2008521806A (en) * 2004-11-30 2008-06-26 アーテシアン セラピューティクス, インコーポレイテッド Compound having mixed PDE-inhibitory activity and β-adrenergic antagonist activity or partial agonist activity for treating heart failure
WO2006060122A2 (en) * 2004-11-30 2006-06-08 Artesian Therapeutics, Inc. Cardiotonic compounds with inhibitory activity against beta-adrenergic receptors and phosphodiesterase
JP2009507792A (en) 2005-08-29 2009-02-26 バーテックス ファーマシューティカルズ インコーポレイテッド 3,5-Disubstituted pyrid-2-ones useful as inhibitors of the TEC family of non-receptor tyrosine kinases
CA2620631A1 (en) 2005-08-29 2007-03-08 Vertex Pharmaceuticals Incorporated 3,5-disubstituted pyrid-2-ones useful as inhibitors of tec family of non-.receptor tyrosine kinases
WO2007027729A1 (en) 2005-08-29 2007-03-08 Vertex Pharmaceuticals Incorporated 3, 5-disubstituted pyrid-2-ones useful as inhibitors of tec family of non-receptor tyrosine kinases
EP1920785A1 (en) 2006-11-07 2008-05-14 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising a complex of pimobendan and cyclodextrin
KR20110089851A (en) * 2008-11-25 2011-08-09 베링거잉겔하임베트메디카게엠베하 Phosphodiesterase type iii(pde iii) inhibitors or ca2+-sensitizing agents for the treatment of hypertrophic cardiomyopathy
GB201017783D0 (en) * 2010-10-21 2010-12-01 Shire Llc Process for the preparation of anagrelide and analogues thereof
EP3167876B1 (en) 2012-03-15 2021-09-08 Boehringer Ingelheim Vetmedica GmbH Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof
KR102455648B1 (en) 2013-07-19 2022-10-19 베링거잉겔하임베트메디카게엠베하 Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
ES2593210T3 (en) 2013-12-04 2016-12-07 Boehringer Ingelheim Vetmedica Gmbh Improved pharmaceutical compositions of pimobendan
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR206801A1 (en) * 1973-02-20 1976-08-23 Ciba Geigy Ag PROCEDURE FOR THE ELABORATION OF DERIVATIVES OF 1-PIRID LOXI-2-HIDROXI-3-AMINO-PROPAN
GB1488330A (en) * 1973-12-19 1977-10-12 Smith Kline French Lab Dihydropyridazinones
JPS5158575A (en) * 1974-11-20 1976-05-21 Nomura Sangyo Kk SHINPUNYORU MOYOTENCHAKUHOHO
JPS51125291A (en) * 1974-12-07 1976-11-01 Otsuka Pharmaceut Co Ltd A process for preparing novel carbostyryl derivatives
JPS5168575A (en) * 1974-12-07 1976-06-14 Otsuka Pharma Co Ltd SHINKIKARUBOSUCHIRIRUJUDOTAINO SEIZOHO
US4111935A (en) * 1975-01-02 1978-09-05 Smith Kline & French Laboratories Limited 3-chloro-6-phenylpyridazine compounds
GB1567907A (en) * 1976-02-09 1980-05-21 Smith Kline French Lab (3-amino-2-hydroxypropoxy)-1-hydrazonophthalazines and pharmaceutical compositions containing them
DE2609645A1 (en) * 1976-03-09 1977-09-15 Boehringer Sohn Ingelheim AMINOALKYLHETEROCYCLES
JPS5919541B2 (en) * 1976-03-17 1984-05-07 大塚製薬株式会社 New 3,4-dihydrocarbostyryl derivative
JPS609713B2 (en) * 1976-10-08 1985-03-12 大塚製薬株式会社 carbostyril derivatives
JPS5919540B2 (en) * 1976-10-13 1984-05-07 大塚製薬株式会社 carbostyril derivatives
JPS5416478A (en) * 1977-07-08 1979-02-07 Otsuka Pharmaceut Co Ltd 3,4-dihydrocarbostyril herivative
DE2948056A1 (en) * 1979-11-29 1981-06-04 Boehringer Mannheim Gmbh, 6800 Mannheim NEW AMINOPROPANOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
DE2950479A1 (en) * 1979-12-14 1981-06-19 A. Nattermann & Cie GmbH, 5000 Köln Beta-adrenolytic 1-amino-3-phenoxy-2-propanol-lactam derivs. - prepd. e.g. by reaction of N-hydroxy:phenyl-lactam with 3-amino-2-hydroxy-propyl halide
DE3023369A1 (en) * 1980-06-23 1982-01-14 Boehringer Mannheim Gmbh, 6800 Mannheim ARYLOXYPROPANOLAMINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
JPS5742673A (en) * 1980-08-29 1982-03-10 Otsuka Pharmaceut Co Ltd Carbostyril derivative
FR2539413A1 (en) * 1983-01-17 1984-07-20 Pos Lab CARBOSTYRILOXIMINOPROPANOLAMINES USEFUL AS MEDICAMENTS AND PROCESS FOR THEIR PREPARATION
US4490371A (en) * 1983-02-16 1984-12-25 Syntex (U.S.A.) Inc. N,N-Disubstituted-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-B]quinazolinyl)oxyalkylamides
GB8323553D0 (en) * 1983-09-02 1983-10-05 Smith Kline French Lab Pharmaceutical compositions
JPS6193169A (en) * 1984-10-12 1986-05-12 Sankyo Co Ltd Pyridazinone derivative and its preparation
US4775674A (en) * 1986-05-23 1988-10-04 Bristol-Myers Company Imidazoquinolinylether derivatives useful as phosphodiesterase and blood aggregation inhibitors
ES2070151T3 (en) * 1988-08-10 1995-06-01 Otsuka Pharma Co Ltd CARDIOTONIC AGENTS.
DE3934436A1 (en) * 1989-06-01 1991-04-18 Thomae Gmbh Dr K 2-HYDROXY-N-PROPYLAMINES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
US5641783A (en) * 1993-11-12 1997-06-24 Cell Therapeutics, Inc. Substituted amino alcohol compounds
US5827893A (en) * 1996-03-29 1998-10-27 Lurie; Keith G. Mechanical and pharmacological therapies to treat cardiac arrest
MXPA04001353A (en) * 2001-08-15 2004-10-27 Icos Corp 2h-phthalazin-1-ones and methods for use thereof.
EP1575923A2 (en) * 2002-12-23 2005-09-21 Artesian Therapeutics, Inc. CARDIOTONIC COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST &bgr;-ADRENERGIC RECEPTORS AND PHOSPHODIESTERASE

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